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Is Resolution of Chronic Pain Associated With Changes in Blood Pressure-related Hypoalgesia?

Is Resolution of Chronic Pain Associated With Changes in Blood Pressure-related Hypoalgesia? Abstract Background In healthy individuals, elevated resting blood pressure (BP) is associated with reduced pain responsiveness and lower temporal summation. Prior work indicates that this BP-related hypoalgesia is reduced in individuals with chronic pain. Purpose This study evaluated whether resolution of chronic pain was associated with greater BP-related hypoalgesia compared to nonresolution. Methods From a prospective sample of adolescents and young adults diagnosed with chronic functional abdominal pain an average of 9 years earlier, 99 individuals in whom the condition had resolved and 51 individuals with ongoing abdominal pain were studied. Resting systolic BP was assessed, followed by evaluation of thermal pain threshold and tolerance, and assessment of temporal summation to thermal pain stimuli. Results Higher resting systolic BP was significantly associated with higher pain threshold and tolerance, and lower temporal summation only in the group with resolved functional abdominal pain (p < .05). Hierarchical regressions revealed that interactions between BP and resolution of chronic pain were significant only for pain tolerance (p < .05). Analyses by sex indicated that interactions between BP and resolution status were significant for the temporal summation outcome in males but not in females. Conclusions Results suggest that BP-related hypoalgesic mechanisms may be more effective in individuals in whom chronic pain has resolved compared to those with ongoing chronic pain. Findings hint at sex differences in the extent to which resolution of chronic pain is associated with BP-related hypoalgesia. Whether greater BP-related hypoalgesia is a consequence of, or alternatively a contributor to, resolution of chronic pain warrants further investigation. Blood pressure, Hypoalgesia, Chronic pain, Resolution, Temporal summation, Functional abdominal pain Introduction An inverse relationship between resting blood pressure (BP) and acute pain responsiveness has been widely demonstrated in normotensive pain-free adults [1–3] and adolescents [4, 5]. This BP-related hypoalgesia has been attributed to a functional inhibitory feedback system [6]. According to this functional model, when pain is experienced, a reflexive increase in sympathetic nervous system arousal is generated, thereby increasing BP levels [7, 8]. These BP increases trigger baroreceptors that activate descending pain inhibitory pathways from the brain to produce analgesic effects and restore cardiovascular homeostasis [9]. Although mechanisms underlying this BP-related hypoalgesia in humans are not fully understood, there is evidence that both endogenous opioid and α2-adrenergic pathways may be involved [10–13]. Several studies have indicated that there may be dysfunction in these BP-hypoalgesic mechanisms in chronic pain patients, reflecting reductions in or absence of normally inverse associations between BP and acute pain sensitivity [14–18]. Although contributors to abnormal interactions between BP and pain modulatory systems in chronic pain patients are not well defined, some have suggested that chronic pain-related changes in descending inhibitory pathways (e.g., endogenous opioids, α2-adrenergic) and baroreflex sensitivity may be involved [17, 18]. It is possible that upregulation of facilitatory ascending pain pathways (reflecting central sensitization) in chronic pain patients also might play a role [19]. Studies examining the interaction between BP and pain regulatory systems in both healthy individuals and those with chronic pain have largely focused on static evoked pain measures, such as pain threshold and tolerance. In contrast, dynamic evoked pain measures, such as temporal summation of pain, are believed to reflect responsiveness of ascending pain facilitatory pathways that are often upregulated in chronic pain patients [19, 20]. Temporal summation has been portrayed as an index of central sensitization [21–23]. In healthy individuals, elevated BP appears linked to reduced temporal summation to evoked pain stimuli in a manner paralleling findings for BP-related inhibition of responses to static evoked pain stimuli [15, 24]. Limited work also suggests that chronic pain patients, in whom elevated temporal summation is typically observed, may exhibit altered associations between resting BP levels and degree of temporal summation [19]. In summary, chronic pain-related dysfunction in BP-related hypoalgesic mechanisms may reflect changes in both descending inhibitory and ascending facilitatory pain pathways. Despite multiple past studies suggesting that there is impairment of BP-related hypoalgesic mechanisms in chronic pain patients, very few studies have specifically examined the long-term effects of chronic pain on these hypoalgesic mechanisms. In work related to this study, we examined whether BP-related hypoalgesia for static evoked pain measures was altered in adolescents and young adults who had been diagnosed with functional abdominal pain (FAP), on average, 9 years earlier compared to similar individuals without any chronic pain history [25]. Results suggested a significant impairment of BP-analgesic mechanisms only for those who had been diagnosed with chronic functional abdominal pain in childhood. A key issue that has not yet been adequately addressed is whether chronic pain-related alterations in BP-hypoalgesic mechanisms remain altered even after the chronic pain resolves. A preliminary, post hoc test of this issue in our past work was confounded by failure to control for comorbid nonabdominal chronic pain in many participants [25]. To address this gap in the literature and build upon our prior work [25–27], in this study, we examined the effect of resolution of chronic pain on BP-related hypoalgesic mechanisms as they relate to responses to both static and dynamic evoked pain stimuli. Specifically, we compared young adults with a known childhood history of functional abdominal pain in whom the condition had resolved versus not resolved at the time of testing, regarding the associations between resting BP and thermal pain threshold, tolerance, and temporal summation. Methods Design This study used a between-subjects design to compare the association between resting BP and both static and dynamic evoked pain responses in adolescents and young adults with a documented history of childhood functional abdominal pain in whom the condition had resolved versus not resolved 9 years after the initial diagnosis. Sample Participants were recruited from a sample participating in a large prospective study of adolescents and young adults with childhood functional abdominal pain [25–27]. Participants from the original study had presented to the Vanderbilt Pediatric Gastroenterology Clinic for evaluation of chronic abdominal pain when they were 8–16 years old. They were enrolled in the primary study based on presence of abdominal pain of at least 3-month duration that was not due to any organic disease (as diagnosed by the physician). Additional details are provided in the study by Walker et al. [27]. This study was conducted an average (±SD) of 8.7 ± 3.40 years after participation in the original study. We sought to provide an optimal test of the relation of chronic pain resolution versus nonresolution to links between resting BP and both static and dynamic evoked pain responsiveness. Therefore, participants in this study included 99 adolescents and young adults (resolved group) who did not report any abdominal or nonabdominal chronic pain conditions in the past 3 months or more on the Persistent Pain Questionnaire (modified to reflect persistent pain in the past 3 months; Walker et al., 2010) [27], and 51 individuals who had ongoing functional abdominal pain complaints without any other comorbid chronic pain conditions (unresolved group). Presence or absence of functional abdominal pain at baseline and at follow-up was determined based on the Rome III symptom-based diagnostic criteria for an abdominal pain-related Functional Gastrointestinal Disorder [28]. Procedure All study procedures were approved by the Vanderbilt Institutional Review Board. All participants took part in the study after providing informed assent/consent. The laboratory study was conducted at the Vanderbilt University Pediatric Clinical Research Center. Participants were asked to avoid using analgesic medications for 12 hr prior to the scheduled study session. In the laboratory, participants completed a 10-min seated rest period during which four resting BP determinations were made using an oscillometric BP cuff (Dinamap Compact-T, Johnson and Johnson, Inc.). The BP variables used in the analyses below reflected the mean of these four resting BP readings. Because previous studies have often shown little association between diastolic BP (DBP) and evoked pain measures [1, 2, 10, 11, 19, 25], the results below focus on the influences of systolic BP (SBP). As expected, analyses for DBP paralleling those described below for SBP revealed no significant main or interaction effects involving DBP (all p > .23; results not detailed). After the resting baseline period, participants engaged in a thermal evoked pain assessment protocol using a Medoc Thermal Sensory Analyzer (TSA-II, Medoc, Inc., Ramat, Israel). This computer-controlled device applied a controlled heat stimulus to the nondominant ventral forearm using a 30 × 30 mm Peltier thermistor probe, as reported in several previous studies [25, 26, 29]. Prior to engaging in the evoked pain tasks, participants were trained in the pain threshold, pain tolerance, and temporal summation protocols used in the study. During the laboratory protocol, four pain threshold trials were conducted, followed by four pain tolerance trials. Target site was slightly different for each trial to avoid local sensitization. Threshold trials started at an adaptation temperature of 32°C, with the temperature increasing at a ramp rate of 0.5°C/s until the participant indicated that the stimulus had begun to feel ‘painful’ (via mouse click). Tolerance trials started at an adaptation temperature of 40°C, with the temperature increasing at the same ramp rate of 0.5°C/s until the participant indicated maximum tolerance had been reached. The interstimulus interval was 25 s for both threshold and tolerance trials. Thermal pain threshold and tolerance variables were generated based on the mean of the four trials for each. After completion of the pain threshold and tolerance assessments, temporal summation trials were conducted using the TSA-II unit with the TPS-CoVAS software (version 3.19, Medoc Inc.). This software administered a standardized oscillating thermal stimulation protocol designed to assess temporal summation [19, 26, 30, 31]. Temporal summation assessment consisted of a sequence of 10 heat pulses applied to the ventral forearm in a fixed location. These 10 successive pulses, of 0.5 s duration each, were administered from a baseline temperature of 40°C rising rapidly to a target temperature of 48°C for each pulse, at a frequency of 0.4 Hz. Previous physiological studies indicate that temporal summation can be elicited with stimuli presented at frequencies ranging between 0.2 and 2.0 Hz [21, 32, 33]. Participants were asked to provide a verbal numeric pain intensity rating using a 0 to 100 scale (anchored with 0 = ‘no pain’ and 100 = ‘worst possible pain’) immediately after the peak of every heat pulse within the sequence. For analyses, the linear slope of the line fitted to the sequence of 10 pain ratings was used as the temporal summation variable. This slope was derived using the sequence of 10 pain ratings regressed on a dummy coded variable with a fixed interval of 1 (range = 1 to 10). This produced an individual slope reflecting the degree of temporal summation of each participant. This slope was used as a dependent variable in the analyses described below. Statistical Analysis All analyses were conducted using the SPSS for Windows Version 24 statistical package (IBM Corp., Armonk, NY). No deviation from normality or homogeneity of variances was observed in any variable in either group, except for sex (p < .05 for both Kolmogorov–Smirnov and Levene’s tests). Group comparisons were conducted with Student’s t test. Associations between SBP and the three thermal pain indices were first examined for both groups using Pearson correlations. Three hierarchical multiple regression analyses were then performed with evoked pain responses as the dependent variable (separately for temporal summation, pain threshold, and pain tolerance) and with participant type (resolved vs. unresolved groups) and SBP as independent variables. For each regression, age and sex were entered as control variables in the first step to control for group differences in age and sex differences in pain outcomes noted in preliminary analyses (all p < .05), with relevant main effects entered in the second step (participant type and SBP variables), and a multiplicative participant type × SBP interaction entered in the third step. The source of significant interactions was determined by examination of simple slopes by participant type. Based on recommendations of Aiken and West [34], regression equations for each participant type, using the hypothetical SBP values of ±1 SD from the observed SBP mean, were calculated to graphically display the significant interactions (simple slopes for resolved and unresolved groups). To further explore possible sex differences in the association of chronic pain resolution with BP-related hypoalgesia, exploratory analyses paralleling the primary analyses described above were conducted separately in female and male participants. The latter approach was used because the cell size for male participants was too small in the unresolved group (n = 18) to permit a reliable comprehensive statistical test of sex-related three-way interactions (i.e., sex × SBP × group). Results Resolved Versus Unresolved Functional Abdominal Pain Group Comparisons Table 1 displays the characteristics of both the resolved and unresolved functional abdominal pain groups. The only significant difference in demographic characteristics between groups was in age (p < .01). The two groups did not differ significantly in terms of evoked pain responsiveness on either the static (pain threshold and tolerance) or dynamic (temporal summation) pain measures (p > .10). Across groups, observed temporal summation slopes exhibited variability, with one-quarter of participants displaying no temporal summation or even habituation (i.e., negative slope; 25th percentile slope = 0.0) and the remainder of the sample displaying evidence for temporal summation (50th percentile slope = 0.84, 75th percentile slope = 1.77). Table 1 Characteristics of Participants by Resolved Versus Unresolved Functional Abdominal Pain Status Variable Participant type Resolved (n = 99) Unresolved (n = 51) Age (years) 20.7 ± 3.47* 18.9 ± 3.17 Sex (N [%])  Females 58 (58.59) 33 (64.71)  Males 41 (41.41) 18 (35.29) Race (N [%])  White 89 (89.90) 49 (96.08)  African-American 8 (8.08) 1 (1.96)  Other 2 (2.02) 1 (1.96) Body mass index 25.6 ± 6.34 24.8 ± 5.76 Regular medication use (N [%]) 29 (29.3) 15 (29.4)  Antidepressant 7 (7.1) 3 (5.9)  Hormonal birth control (female) 7 (12.1) 4 (12.1) SBP (mmHg) 112.5 ± 13.06 113.0 ± 11.60 DBP (mmHg) 61.9 ± 7.51 61.4 ± 7.54 Temporal summation slope 1.0 ± 1.55 1.1 ± 1.84 Thermal pain threshold (°C) 41.7 ± 3.20 41.7 ± 3.06 Thermal pain tolerance (°C) 47.1 ± 2.17 46.9 ± 1.53 Variable Participant type Resolved (n = 99) Unresolved (n = 51) Age (years) 20.7 ± 3.47* 18.9 ± 3.17 Sex (N [%])  Females 58 (58.59) 33 (64.71)  Males 41 (41.41) 18 (35.29) Race (N [%])  White 89 (89.90) 49 (96.08)  African-American 8 (8.08) 1 (1.96)  Other 2 (2.02) 1 (1.96) Body mass index 25.6 ± 6.34 24.8 ± 5.76 Regular medication use (N [%]) 29 (29.3) 15 (29.4)  Antidepressant 7 (7.1) 3 (5.9)  Hormonal birth control (female) 7 (12.1) 4 (12.1) SBP (mmHg) 112.5 ± 13.06 113.0 ± 11.60 DBP (mmHg) 61.9 ± 7.51 61.4 ± 7.54 Temporal summation slope 1.0 ± 1.55 1.1 ± 1.84 Thermal pain threshold (°C) 41.7 ± 3.20 41.7 ± 3.06 Thermal pain tolerance (°C) 47.1 ± 2.17 46.9 ± 1.53 All means are presented as mean ± SD. SBP systolic blood pressure; DBP diastolic blood pressure. *p < .01. View Large Table 1 Characteristics of Participants by Resolved Versus Unresolved Functional Abdominal Pain Status Variable Participant type Resolved (n = 99) Unresolved (n = 51) Age (years) 20.7 ± 3.47* 18.9 ± 3.17 Sex (N [%])  Females 58 (58.59) 33 (64.71)  Males 41 (41.41) 18 (35.29) Race (N [%])  White 89 (89.90) 49 (96.08)  African-American 8 (8.08) 1 (1.96)  Other 2 (2.02) 1 (1.96) Body mass index 25.6 ± 6.34 24.8 ± 5.76 Regular medication use (N [%]) 29 (29.3) 15 (29.4)  Antidepressant 7 (7.1) 3 (5.9)  Hormonal birth control (female) 7 (12.1) 4 (12.1) SBP (mmHg) 112.5 ± 13.06 113.0 ± 11.60 DBP (mmHg) 61.9 ± 7.51 61.4 ± 7.54 Temporal summation slope 1.0 ± 1.55 1.1 ± 1.84 Thermal pain threshold (°C) 41.7 ± 3.20 41.7 ± 3.06 Thermal pain tolerance (°C) 47.1 ± 2.17 46.9 ± 1.53 Variable Participant type Resolved (n = 99) Unresolved (n = 51) Age (years) 20.7 ± 3.47* 18.9 ± 3.17 Sex (N [%])  Females 58 (58.59) 33 (64.71)  Males 41 (41.41) 18 (35.29) Race (N [%])  White 89 (89.90) 49 (96.08)  African-American 8 (8.08) 1 (1.96)  Other 2 (2.02) 1 (1.96) Body mass index 25.6 ± 6.34 24.8 ± 5.76 Regular medication use (N [%]) 29 (29.3) 15 (29.4)  Antidepressant 7 (7.1) 3 (5.9)  Hormonal birth control (female) 7 (12.1) 4 (12.1) SBP (mmHg) 112.5 ± 13.06 113.0 ± 11.60 DBP (mmHg) 61.9 ± 7.51 61.4 ± 7.54 Temporal summation slope 1.0 ± 1.55 1.1 ± 1.84 Thermal pain threshold (°C) 41.7 ± 3.20 41.7 ± 3.06 Thermal pain tolerance (°C) 47.1 ± 2.17 46.9 ± 1.53 All means are presented as mean ± SD. SBP systolic blood pressure; DBP diastolic blood pressure. *p < .01. View Large Correlation Analyses Simple correlations between SBP and thermal pain indices are displayed by participant type in Table 2. Resting SBP was significantly associated with all static and dynamic pain measures only in the resolved group. As expected based on prior work in pain-free individuals [1,3–5], SBP was inversely associated with temporal summation and positively associated with thermal pain threshold and tolerance in participants in whom functional abdominal pain had resolved. Table 2 Zero-order Correlations Between Resting Systolic Blood Pressure and Static and Dynamic Evoked Pain Outcomes by Resolved Versus Unresolved Functional Abdominal Pain Status Resting systolic blood pressure Resolved Unresolved Temporal summation slope −0.31** −0.20 Thermal pain threshold (°C) 0.24* 0.01 Thermal pain tolerance (°C) 0.41*** 0.13 Resting systolic blood pressure Resolved Unresolved Temporal summation slope −0.31** −0.20 Thermal pain threshold (°C) 0.24* 0.01 Thermal pain tolerance (°C) 0.41*** 0.13 *p < .05. **p < .01. ***p < .001. View Large Table 2 Zero-order Correlations Between Resting Systolic Blood Pressure and Static and Dynamic Evoked Pain Outcomes by Resolved Versus Unresolved Functional Abdominal Pain Status Resting systolic blood pressure Resolved Unresolved Temporal summation slope −0.31** −0.20 Thermal pain threshold (°C) 0.24* 0.01 Thermal pain tolerance (°C) 0.41*** 0.13 Resting systolic blood pressure Resolved Unresolved Temporal summation slope −0.31** −0.20 Thermal pain threshold (°C) 0.24* 0.01 Thermal pain tolerance (°C) 0.41*** 0.13 *p < .05. **p < .01. ***p < .001. View Large Hierarchical Regression Analyses Hierarchical multiple regression, controlling for main effects of age and sex, targeting thermal pain tolerance as the dependent variable revealed a significant participant type × SBP interaction (R2 increment = 0.02, F change (1,144) = 4.03, p < .05). As shown in Fig. 1, simple- effects analyses indicated that this interaction was due to a significant positive association between SBP and thermal pain tolerance in the resolved group (Beta = 0.405, t(98) = 4.359, p < .001) that was notably smaller and nonsignificant in the unresolved group (Beta = 0.130, t(50) = 0.919, p > .36). These findings for thermal pain tolerance suggest that BP-related hypoalgesic mechanisms may function more effectively in participants in whom functional abdominal pain has resolved than in those in whom it has not resolved. Fig. 1 View largeDownload slide Effect of resting systolic blood pressure (SBP) on thermal pain tolerance by resolved versus unresolved functional abdominal pain status. SBP values reflect values one standard deviation below (low SBP) and above (high SBP) the observed SBP mean. Fig. 1 View largeDownload slide Effect of resting systolic blood pressure (SBP) on thermal pain tolerance by resolved versus unresolved functional abdominal pain status. SBP values reflect values one standard deviation below (low SBP) and above (high SBP) the observed SBP mean. In contrast, the participant type × SBP interaction was nonsignificant in a regression in which thermal pain threshold was the dependent variable (R2 increment = 0.010, F change (1,143) = 1.50, p > .22). There was also no significant main effect of SBP on the thermal pain threshold outcome across the resolved and unresolved groups (Beta = 0.10, t(144) = 1.08, p > .28). Hierarchical multiple regression with the dynamic evoked pain outcome (temporal summation) as the dependent variable revealed a significant main effect for SBP, such that greater SBP was associated with lower temporal summation across the resolved and unresolved groups (Beta = −0.19, t(145) = −2.07, p < .05). For analyses of the temporal summation outcome, no significant participant type × SBP interaction was observed (R2 increment < 0.001, F change (1,144) = 0.03, p > .85). Possible Sex Differences Although limited by statistical power due to the small male subsample, the hierarchical regression analyses reported above were conducted again separately for males and females to address possible sex differences in BP-related hypoalgesia as a function of whether functional abdominal pain had resolved. In males, the participant type × SBP interaction for the temporal summation outcome was significant (R2 increment = 0.075, F change (1,55) = 4.434, p < .05). Simple-effect analyses indicated that this significant interaction in males was due to a nonsignificant trend for an inverse association between SBP and temporal summation in the resolved group (Beta = −0.283, t(38) = −1.725, p < .10) and a nonsignificant positive association in the unresolved group (Beta = 0.291, t(17) = 1.180, p > .25). For males, the participant type × SBP interaction was nonsignificant for both pain threshold (R2 increment = 0.016, F change (1,55) = 0.870, p > .35) and pain tolerance (R2 increment < 0.001, F change (1,55) = 0.015, p > .90). Parallel analyses in female participants revealed no significant participant type × SBP interaction for temporal summation (R2 increment = 0.020, F change (1,87) = 1.839, p > .17), pain threshold (R2 increment = 0.001, F change (1,87) = 0.051, p > .82), or pain tolerance (R2 increment = 0.022, F change (1,87) = 2.083, p > .15). Discussion BP-related hypoalgesia has been reliably demonstrated in normotensive pain-free individuals across the life span [3–5, 25, 35, 36]. Dysfunction in these BP-related hypoalgesic mechanisms has been evidenced in individuals experiencing chronic pain [14–18, 37]. To our knowledge, however, no prior study has adequately explored whether resolution of chronic pain is associated with the extent of BP-related hypoalgesia. To address this gap in the literature, we examined in adolescents and young adults who had suffered from chronic functional abdominal pain during childhood whether resolution versus nonresolution of this chronic pain condition was associated with different patterns of BP-related hypoalgesia. In addition, we explored the impact of chronic pain resolution not only in terms of responses to commonly reported static evoked pain measures but also regarding responses to dynamic evoked pain assessment (temporal summation) that are infrequently examined in relation to BP-linked hypoalgesia. We found significant correlations between SBP and both static and dynamic pain measures only in individuals in whom chronic pain had resolved. Specifically, SBP was significantly and positively associated with thermal pain threshold and tolerance and inversely associated with temporal summation in the pediatric-onset functional abdominal pain patients who were no longer experiencing chronic pain of any kind 9 years later. In contrast, significant BP-related hypoalgesic effects were not observed for any of these evoked pain outcomes in individuals with ongoing chronic functional abdominal pain. This pattern is consistent with the view that recovery from chronic pain might normalize BP-hypoalgesic function, although the interaction of resolution status with SBP was significant only for the thermal pain tolerance outcome. This latter finding indicates that pain tolerance was the evoked pain outcome most sensitive to associations between the resolution of chronic pain and extent of BP-related hypoalgesia. We had previously reported evidence for dysfunction of BP-related hypoalgesic mechanisms in young adults with a history of pediatric-onset functional abdominal pain [25]. In post-hoc analyses in this prior work using a smaller sample that only partially overlapped with this study, we reported that associations between resting SBP and pain threshold and tolerance outcomes did not differ significantly between subjects with ongoing functional abdominal pain (n = 35) and those in whom the condition had resolved (n = 60). A critical distinction between this prior work and this study should be noted, however. In this work, the total sample from which participants were drawn had increased substantially from what was available in 2010. As a result, this study permitted us to be more selective and provided a more defensible test of links between chronic pain resolution and BP-related hypoalgesia. Specifically, the larger total sample available for this study allowed us to contrast subjects with ongoing functional abdominal pain alone (with no other comorbid chronic pain; n = 51) versus those with resolved functional abdominal pain who had no other ongoing chronic pain complaints (n = 99). Thus, the current findings reflect not only a larger and statistically more powerful sample than the 2010 study but a sample entirely free of other comorbid chronic pain conditions that likely confounded results in our prior report. As a result, this article provides a higher quality test of hypotheses regarding the association of chronic pain resolution with extent of BP-related hypoalgesia than reported in our previous work [25]. The current findings suggest that BP-related hypoalgesic mechanisms may be more effective in individuals in whom chronic pain has resolved as compared to those in whom chronic pain has not resolved. Perhaps, individuals who recover from chronic pain not only have a cessation of ongoing pain but also experience a restoration of BP-related hypoalgesic mechanisms, which in turn may enhance their ability to adapt to subsequent acutely painful experiences. Alternatively, it is possible that chronic pain is more likely to resolve in individuals with more effective BP-related hypoalgesia. Because this study did not assess these hypoalgesic mechanisms at the time of initial functional abdominal pain diagnosis in childhood, it is not possible to ascertain which of these explanations is correct. Reasons for BP-related hypoalgesia being more effective in individuals in whom chronic pain has resolved are not yet known. Mechanisms involved in this hypoalgesia are believed to include endogenous opioidergic inhibition, alpha-2 adrenergic inhibition, and baroreflex sensitivity [10–13, 17, 18]. It has been hypothesized that reductions in BP-related hypoalgesia associated with chronic pain may derive from a combination of chronic pain-related decrements in these mechanisms, for example, impairments of endogenous inhibitory systems due to chronically excessive demands as chronic pain taxes homeostatic systems [9]. We can speculate that if these decrements are a result of chronic pain rather than a contributor, then resolution of chronic pain might help restore these systems, thereby normalizing BP-related hypoalgesia. This study design did not allow for determination of the causes of the less-effective BP-related hypoalgesia in individuals with ongoing chronic pain or the factors underlying apparent normalization of these adaptive systems once chronic pain resolves. Given evidence that chronic pain in adults may increase hypertension risk in part via mechanisms that also underlie BP-related hypoalgesia [37], replication of the current results in adults might imply that successful chronic pain management could help reduce comorbid hypertension risk in the chronic pain population. Measurement of both static (thermal pain threshold and tolerance) and dynamic (temporal summation) evoked pain outcomes allowed us to explore whether chronic pain-related alterations in BP-related hypoalgesia might derive from broad impairments in this BP-analgesic system or instead might be specifically associated with differences in BP-related inhibitory effects on ascending pain facilitation (i.e., temporal summation outcomes) like those that have been reported elsewhere [19]. Based on the absence of significant differences in links between resting BP and temporal summation as a function of chronic pain resolution status and the stronger resolution-related effects observed for the influence of resting BP on thermal pain tolerance, results seem to argue against central sensitization processes being a major contributor to alterations in BP-related hypoalgesic mechanism associated with chronic pain. Some prior work suggested that degree of BP-related hypoalgesia might differ by sex [36]; therefore, we explored the possibility that the relationship between chronic pain resolution and BP-related hypoalgesic mechanisms might differ in males and females. Indeed, analyses yielded some suggestive evidence for sex specificity. In males only, a significant participant type × SBP interaction was observed, specifically for temporal summation. Although the simple effects comprising this interaction did not reach statistical significance, results suggested that differences in associations between elevated SBP and reduced temporal summation across resolved and unresolved groups might be particularly notable among male FAP participants. The small size of the sample of males relative to females, however, limits the conclusions that can be made with regard to sex differences. To eliminate the possible confounding effects of suffering from comorbid chronic pain unrelated to functional abdominal pain, we excluded participants reporting any other forms of chronic pain from both groups. Nonetheless, this study has several potential limitations. First, there was a significant between-group difference in age, although the absolute difference in age between the resolved and unresolved groups was less than 2 years. Although it is not clear whether this difference was large enough to substantively affect the results, we do note that all hierarchical regression analyses statistically controlled for these age differences. Second, as noted previously, the sample size available did not have optimal statistical power for permitting definitive evaluations of any sex differences in the association of chronic pain resolution with extent of BP-related hypoalgesia. In summary, this study suggested better functioning in BP-related hypoalgesic mechanisms in young adults in whom childhood-onset, chronic functional abdominal pain had resolved compared with those in whom it had not resolved. Greater resting SBP was significantly linked to higher pain threshold, higher pain tolerance, and lower temporal summation in individuals in whom chronic pain had resolved, but not in those in whom it had not resolved. The magnitude of differences between resolved versus unresolved groups was largest for pain tolerance outcomes. The relation of chronic pain resolution status to associations between resting SBP and temporal summation (a hypothesized index of central sensitization) was more evident in males than in females. Future studies are needed to elucidate the mechanisms contributing to differing BP-related hypoalgesia patterns in those who recover versus fail to recover from chronic pain in childhood. Acknowledgements This research was supported by grants from the National Institutes of Health, including R01 HD23264 and R01 HD76983 (LSW), Vanderbilt Kennedy Center (P30 HD15052), Vanderbilt Digestive Disease Research Center (DK058404), and Vanderbilt CTSA (UL 1 RR024975); and a predoctoral fellowship (FPU13/03630) from the Spanish government (PDLC). Compliance with Ethical Standards Authors’ Statement of Conflict of Interest and Adherence to Ethical Standards Authors Pablo de la Coba, Stephen Bruehl, Judy Garber, Craig A. Smith, and Lynn S. Walker declare that they have no conflict of interest. All procedures, including the informed consent process, were conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Authors' Contributions P.C. contributed to conception and design of the study, conducted analyses, interpreted data, helped draft and revise the manuscript, and gave final approval of the submitted manuscript. S.B. contributed to conception and design of the study, assisted in conducting analyses and interpreting data, contributed to drafting and critically revising the manuscript, and approved the final version of the submitted manuscript. J.G. contributed to conception and design of the study, assisted in critically revising the manuscript, and approved the final version of the submitted manuscript. C.S. contributed to conception and design of the study, assisted in critically revising the manuscript, and approved the final version of the submitted manuscript. L.W. contributed to conception and design of the study, assisted in critically revising the manuscript, and approved the final version of the submitted manuscript. Ethical Approval The authors confirm that all procedures contained in this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. Ethical approval for all study procedures was provided by the Vanderbilt University Institutional Review Board. Informed Consent All participants provided written informed assent/consent prior to participating in this research. References 1. 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Is Resolution of Chronic Pain Associated With Changes in Blood Pressure-related Hypoalgesia?

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Abstract

Abstract Background In healthy individuals, elevated resting blood pressure (BP) is associated with reduced pain responsiveness and lower temporal summation. Prior work indicates that this BP-related hypoalgesia is reduced in individuals with chronic pain. Purpose This study evaluated whether resolution of chronic pain was associated with greater BP-related hypoalgesia compared to nonresolution. Methods From a prospective sample of adolescents and young adults diagnosed with chronic functional abdominal pain an average of 9 years earlier, 99 individuals in whom the condition had resolved and 51 individuals with ongoing abdominal pain were studied. Resting systolic BP was assessed, followed by evaluation of thermal pain threshold and tolerance, and assessment of temporal summation to thermal pain stimuli. Results Higher resting systolic BP was significantly associated with higher pain threshold and tolerance, and lower temporal summation only in the group with resolved functional abdominal pain (p < .05). Hierarchical regressions revealed that interactions between BP and resolution of chronic pain were significant only for pain tolerance (p < .05). Analyses by sex indicated that interactions between BP and resolution status were significant for the temporal summation outcome in males but not in females. Conclusions Results suggest that BP-related hypoalgesic mechanisms may be more effective in individuals in whom chronic pain has resolved compared to those with ongoing chronic pain. Findings hint at sex differences in the extent to which resolution of chronic pain is associated with BP-related hypoalgesia. Whether greater BP-related hypoalgesia is a consequence of, or alternatively a contributor to, resolution of chronic pain warrants further investigation. Blood pressure, Hypoalgesia, Chronic pain, Resolution, Temporal summation, Functional abdominal pain Introduction An inverse relationship between resting blood pressure (BP) and acute pain responsiveness has been widely demonstrated in normotensive pain-free adults [1–3] and adolescents [4, 5]. This BP-related hypoalgesia has been attributed to a functional inhibitory feedback system [6]. According to this functional model, when pain is experienced, a reflexive increase in sympathetic nervous system arousal is generated, thereby increasing BP levels [7, 8]. These BP increases trigger baroreceptors that activate descending pain inhibitory pathways from the brain to produce analgesic effects and restore cardiovascular homeostasis [9]. Although mechanisms underlying this BP-related hypoalgesia in humans are not fully understood, there is evidence that both endogenous opioid and α2-adrenergic pathways may be involved [10–13]. Several studies have indicated that there may be dysfunction in these BP-hypoalgesic mechanisms in chronic pain patients, reflecting reductions in or absence of normally inverse associations between BP and acute pain sensitivity [14–18]. Although contributors to abnormal interactions between BP and pain modulatory systems in chronic pain patients are not well defined, some have suggested that chronic pain-related changes in descending inhibitory pathways (e.g., endogenous opioids, α2-adrenergic) and baroreflex sensitivity may be involved [17, 18]. It is possible that upregulation of facilitatory ascending pain pathways (reflecting central sensitization) in chronic pain patients also might play a role [19]. Studies examining the interaction between BP and pain regulatory systems in both healthy individuals and those with chronic pain have largely focused on static evoked pain measures, such as pain threshold and tolerance. In contrast, dynamic evoked pain measures, such as temporal summation of pain, are believed to reflect responsiveness of ascending pain facilitatory pathways that are often upregulated in chronic pain patients [19, 20]. Temporal summation has been portrayed as an index of central sensitization [21–23]. In healthy individuals, elevated BP appears linked to reduced temporal summation to evoked pain stimuli in a manner paralleling findings for BP-related inhibition of responses to static evoked pain stimuli [15, 24]. Limited work also suggests that chronic pain patients, in whom elevated temporal summation is typically observed, may exhibit altered associations between resting BP levels and degree of temporal summation [19]. In summary, chronic pain-related dysfunction in BP-related hypoalgesic mechanisms may reflect changes in both descending inhibitory and ascending facilitatory pain pathways. Despite multiple past studies suggesting that there is impairment of BP-related hypoalgesic mechanisms in chronic pain patients, very few studies have specifically examined the long-term effects of chronic pain on these hypoalgesic mechanisms. In work related to this study, we examined whether BP-related hypoalgesia for static evoked pain measures was altered in adolescents and young adults who had been diagnosed with functional abdominal pain (FAP), on average, 9 years earlier compared to similar individuals without any chronic pain history [25]. Results suggested a significant impairment of BP-analgesic mechanisms only for those who had been diagnosed with chronic functional abdominal pain in childhood. A key issue that has not yet been adequately addressed is whether chronic pain-related alterations in BP-hypoalgesic mechanisms remain altered even after the chronic pain resolves. A preliminary, post hoc test of this issue in our past work was confounded by failure to control for comorbid nonabdominal chronic pain in many participants [25]. To address this gap in the literature and build upon our prior work [25–27], in this study, we examined the effect of resolution of chronic pain on BP-related hypoalgesic mechanisms as they relate to responses to both static and dynamic evoked pain stimuli. Specifically, we compared young adults with a known childhood history of functional abdominal pain in whom the condition had resolved versus not resolved at the time of testing, regarding the associations between resting BP and thermal pain threshold, tolerance, and temporal summation. Methods Design This study used a between-subjects design to compare the association between resting BP and both static and dynamic evoked pain responses in adolescents and young adults with a documented history of childhood functional abdominal pain in whom the condition had resolved versus not resolved 9 years after the initial diagnosis. Sample Participants were recruited from a sample participating in a large prospective study of adolescents and young adults with childhood functional abdominal pain [25–27]. Participants from the original study had presented to the Vanderbilt Pediatric Gastroenterology Clinic for evaluation of chronic abdominal pain when they were 8–16 years old. They were enrolled in the primary study based on presence of abdominal pain of at least 3-month duration that was not due to any organic disease (as diagnosed by the physician). Additional details are provided in the study by Walker et al. [27]. This study was conducted an average (±SD) of 8.7 ± 3.40 years after participation in the original study. We sought to provide an optimal test of the relation of chronic pain resolution versus nonresolution to links between resting BP and both static and dynamic evoked pain responsiveness. Therefore, participants in this study included 99 adolescents and young adults (resolved group) who did not report any abdominal or nonabdominal chronic pain conditions in the past 3 months or more on the Persistent Pain Questionnaire (modified to reflect persistent pain in the past 3 months; Walker et al., 2010) [27], and 51 individuals who had ongoing functional abdominal pain complaints without any other comorbid chronic pain conditions (unresolved group). Presence or absence of functional abdominal pain at baseline and at follow-up was determined based on the Rome III symptom-based diagnostic criteria for an abdominal pain-related Functional Gastrointestinal Disorder [28]. Procedure All study procedures were approved by the Vanderbilt Institutional Review Board. All participants took part in the study after providing informed assent/consent. The laboratory study was conducted at the Vanderbilt University Pediatric Clinical Research Center. Participants were asked to avoid using analgesic medications for 12 hr prior to the scheduled study session. In the laboratory, participants completed a 10-min seated rest period during which four resting BP determinations were made using an oscillometric BP cuff (Dinamap Compact-T, Johnson and Johnson, Inc.). The BP variables used in the analyses below reflected the mean of these four resting BP readings. Because previous studies have often shown little association between diastolic BP (DBP) and evoked pain measures [1, 2, 10, 11, 19, 25], the results below focus on the influences of systolic BP (SBP). As expected, analyses for DBP paralleling those described below for SBP revealed no significant main or interaction effects involving DBP (all p > .23; results not detailed). After the resting baseline period, participants engaged in a thermal evoked pain assessment protocol using a Medoc Thermal Sensory Analyzer (TSA-II, Medoc, Inc., Ramat, Israel). This computer-controlled device applied a controlled heat stimulus to the nondominant ventral forearm using a 30 × 30 mm Peltier thermistor probe, as reported in several previous studies [25, 26, 29]. Prior to engaging in the evoked pain tasks, participants were trained in the pain threshold, pain tolerance, and temporal summation protocols used in the study. During the laboratory protocol, four pain threshold trials were conducted, followed by four pain tolerance trials. Target site was slightly different for each trial to avoid local sensitization. Threshold trials started at an adaptation temperature of 32°C, with the temperature increasing at a ramp rate of 0.5°C/s until the participant indicated that the stimulus had begun to feel ‘painful’ (via mouse click). Tolerance trials started at an adaptation temperature of 40°C, with the temperature increasing at the same ramp rate of 0.5°C/s until the participant indicated maximum tolerance had been reached. The interstimulus interval was 25 s for both threshold and tolerance trials. Thermal pain threshold and tolerance variables were generated based on the mean of the four trials for each. After completion of the pain threshold and tolerance assessments, temporal summation trials were conducted using the TSA-II unit with the TPS-CoVAS software (version 3.19, Medoc Inc.). This software administered a standardized oscillating thermal stimulation protocol designed to assess temporal summation [19, 26, 30, 31]. Temporal summation assessment consisted of a sequence of 10 heat pulses applied to the ventral forearm in a fixed location. These 10 successive pulses, of 0.5 s duration each, were administered from a baseline temperature of 40°C rising rapidly to a target temperature of 48°C for each pulse, at a frequency of 0.4 Hz. Previous physiological studies indicate that temporal summation can be elicited with stimuli presented at frequencies ranging between 0.2 and 2.0 Hz [21, 32, 33]. Participants were asked to provide a verbal numeric pain intensity rating using a 0 to 100 scale (anchored with 0 = ‘no pain’ and 100 = ‘worst possible pain’) immediately after the peak of every heat pulse within the sequence. For analyses, the linear slope of the line fitted to the sequence of 10 pain ratings was used as the temporal summation variable. This slope was derived using the sequence of 10 pain ratings regressed on a dummy coded variable with a fixed interval of 1 (range = 1 to 10). This produced an individual slope reflecting the degree of temporal summation of each participant. This slope was used as a dependent variable in the analyses described below. Statistical Analysis All analyses were conducted using the SPSS for Windows Version 24 statistical package (IBM Corp., Armonk, NY). No deviation from normality or homogeneity of variances was observed in any variable in either group, except for sex (p < .05 for both Kolmogorov–Smirnov and Levene’s tests). Group comparisons were conducted with Student’s t test. Associations between SBP and the three thermal pain indices were first examined for both groups using Pearson correlations. Three hierarchical multiple regression analyses were then performed with evoked pain responses as the dependent variable (separately for temporal summation, pain threshold, and pain tolerance) and with participant type (resolved vs. unresolved groups) and SBP as independent variables. For each regression, age and sex were entered as control variables in the first step to control for group differences in age and sex differences in pain outcomes noted in preliminary analyses (all p < .05), with relevant main effects entered in the second step (participant type and SBP variables), and a multiplicative participant type × SBP interaction entered in the third step. The source of significant interactions was determined by examination of simple slopes by participant type. Based on recommendations of Aiken and West [34], regression equations for each participant type, using the hypothetical SBP values of ±1 SD from the observed SBP mean, were calculated to graphically display the significant interactions (simple slopes for resolved and unresolved groups). To further explore possible sex differences in the association of chronic pain resolution with BP-related hypoalgesia, exploratory analyses paralleling the primary analyses described above were conducted separately in female and male participants. The latter approach was used because the cell size for male participants was too small in the unresolved group (n = 18) to permit a reliable comprehensive statistical test of sex-related three-way interactions (i.e., sex × SBP × group). Results Resolved Versus Unresolved Functional Abdominal Pain Group Comparisons Table 1 displays the characteristics of both the resolved and unresolved functional abdominal pain groups. The only significant difference in demographic characteristics between groups was in age (p < .01). The two groups did not differ significantly in terms of evoked pain responsiveness on either the static (pain threshold and tolerance) or dynamic (temporal summation) pain measures (p > .10). Across groups, observed temporal summation slopes exhibited variability, with one-quarter of participants displaying no temporal summation or even habituation (i.e., negative slope; 25th percentile slope = 0.0) and the remainder of the sample displaying evidence for temporal summation (50th percentile slope = 0.84, 75th percentile slope = 1.77). Table 1 Characteristics of Participants by Resolved Versus Unresolved Functional Abdominal Pain Status Variable Participant type Resolved (n = 99) Unresolved (n = 51) Age (years) 20.7 ± 3.47* 18.9 ± 3.17 Sex (N [%])  Females 58 (58.59) 33 (64.71)  Males 41 (41.41) 18 (35.29) Race (N [%])  White 89 (89.90) 49 (96.08)  African-American 8 (8.08) 1 (1.96)  Other 2 (2.02) 1 (1.96) Body mass index 25.6 ± 6.34 24.8 ± 5.76 Regular medication use (N [%]) 29 (29.3) 15 (29.4)  Antidepressant 7 (7.1) 3 (5.9)  Hormonal birth control (female) 7 (12.1) 4 (12.1) SBP (mmHg) 112.5 ± 13.06 113.0 ± 11.60 DBP (mmHg) 61.9 ± 7.51 61.4 ± 7.54 Temporal summation slope 1.0 ± 1.55 1.1 ± 1.84 Thermal pain threshold (°C) 41.7 ± 3.20 41.7 ± 3.06 Thermal pain tolerance (°C) 47.1 ± 2.17 46.9 ± 1.53 Variable Participant type Resolved (n = 99) Unresolved (n = 51) Age (years) 20.7 ± 3.47* 18.9 ± 3.17 Sex (N [%])  Females 58 (58.59) 33 (64.71)  Males 41 (41.41) 18 (35.29) Race (N [%])  White 89 (89.90) 49 (96.08)  African-American 8 (8.08) 1 (1.96)  Other 2 (2.02) 1 (1.96) Body mass index 25.6 ± 6.34 24.8 ± 5.76 Regular medication use (N [%]) 29 (29.3) 15 (29.4)  Antidepressant 7 (7.1) 3 (5.9)  Hormonal birth control (female) 7 (12.1) 4 (12.1) SBP (mmHg) 112.5 ± 13.06 113.0 ± 11.60 DBP (mmHg) 61.9 ± 7.51 61.4 ± 7.54 Temporal summation slope 1.0 ± 1.55 1.1 ± 1.84 Thermal pain threshold (°C) 41.7 ± 3.20 41.7 ± 3.06 Thermal pain tolerance (°C) 47.1 ± 2.17 46.9 ± 1.53 All means are presented as mean ± SD. SBP systolic blood pressure; DBP diastolic blood pressure. *p < .01. View Large Table 1 Characteristics of Participants by Resolved Versus Unresolved Functional Abdominal Pain Status Variable Participant type Resolved (n = 99) Unresolved (n = 51) Age (years) 20.7 ± 3.47* 18.9 ± 3.17 Sex (N [%])  Females 58 (58.59) 33 (64.71)  Males 41 (41.41) 18 (35.29) Race (N [%])  White 89 (89.90) 49 (96.08)  African-American 8 (8.08) 1 (1.96)  Other 2 (2.02) 1 (1.96) Body mass index 25.6 ± 6.34 24.8 ± 5.76 Regular medication use (N [%]) 29 (29.3) 15 (29.4)  Antidepressant 7 (7.1) 3 (5.9)  Hormonal birth control (female) 7 (12.1) 4 (12.1) SBP (mmHg) 112.5 ± 13.06 113.0 ± 11.60 DBP (mmHg) 61.9 ± 7.51 61.4 ± 7.54 Temporal summation slope 1.0 ± 1.55 1.1 ± 1.84 Thermal pain threshold (°C) 41.7 ± 3.20 41.7 ± 3.06 Thermal pain tolerance (°C) 47.1 ± 2.17 46.9 ± 1.53 Variable Participant type Resolved (n = 99) Unresolved (n = 51) Age (years) 20.7 ± 3.47* 18.9 ± 3.17 Sex (N [%])  Females 58 (58.59) 33 (64.71)  Males 41 (41.41) 18 (35.29) Race (N [%])  White 89 (89.90) 49 (96.08)  African-American 8 (8.08) 1 (1.96)  Other 2 (2.02) 1 (1.96) Body mass index 25.6 ± 6.34 24.8 ± 5.76 Regular medication use (N [%]) 29 (29.3) 15 (29.4)  Antidepressant 7 (7.1) 3 (5.9)  Hormonal birth control (female) 7 (12.1) 4 (12.1) SBP (mmHg) 112.5 ± 13.06 113.0 ± 11.60 DBP (mmHg) 61.9 ± 7.51 61.4 ± 7.54 Temporal summation slope 1.0 ± 1.55 1.1 ± 1.84 Thermal pain threshold (°C) 41.7 ± 3.20 41.7 ± 3.06 Thermal pain tolerance (°C) 47.1 ± 2.17 46.9 ± 1.53 All means are presented as mean ± SD. SBP systolic blood pressure; DBP diastolic blood pressure. *p < .01. View Large Correlation Analyses Simple correlations between SBP and thermal pain indices are displayed by participant type in Table 2. Resting SBP was significantly associated with all static and dynamic pain measures only in the resolved group. As expected based on prior work in pain-free individuals [1,3–5], SBP was inversely associated with temporal summation and positively associated with thermal pain threshold and tolerance in participants in whom functional abdominal pain had resolved. Table 2 Zero-order Correlations Between Resting Systolic Blood Pressure and Static and Dynamic Evoked Pain Outcomes by Resolved Versus Unresolved Functional Abdominal Pain Status Resting systolic blood pressure Resolved Unresolved Temporal summation slope −0.31** −0.20 Thermal pain threshold (°C) 0.24* 0.01 Thermal pain tolerance (°C) 0.41*** 0.13 Resting systolic blood pressure Resolved Unresolved Temporal summation slope −0.31** −0.20 Thermal pain threshold (°C) 0.24* 0.01 Thermal pain tolerance (°C) 0.41*** 0.13 *p < .05. **p < .01. ***p < .001. View Large Table 2 Zero-order Correlations Between Resting Systolic Blood Pressure and Static and Dynamic Evoked Pain Outcomes by Resolved Versus Unresolved Functional Abdominal Pain Status Resting systolic blood pressure Resolved Unresolved Temporal summation slope −0.31** −0.20 Thermal pain threshold (°C) 0.24* 0.01 Thermal pain tolerance (°C) 0.41*** 0.13 Resting systolic blood pressure Resolved Unresolved Temporal summation slope −0.31** −0.20 Thermal pain threshold (°C) 0.24* 0.01 Thermal pain tolerance (°C) 0.41*** 0.13 *p < .05. **p < .01. ***p < .001. View Large Hierarchical Regression Analyses Hierarchical multiple regression, controlling for main effects of age and sex, targeting thermal pain tolerance as the dependent variable revealed a significant participant type × SBP interaction (R2 increment = 0.02, F change (1,144) = 4.03, p < .05). As shown in Fig. 1, simple- effects analyses indicated that this interaction was due to a significant positive association between SBP and thermal pain tolerance in the resolved group (Beta = 0.405, t(98) = 4.359, p < .001) that was notably smaller and nonsignificant in the unresolved group (Beta = 0.130, t(50) = 0.919, p > .36). These findings for thermal pain tolerance suggest that BP-related hypoalgesic mechanisms may function more effectively in participants in whom functional abdominal pain has resolved than in those in whom it has not resolved. Fig. 1 View largeDownload slide Effect of resting systolic blood pressure (SBP) on thermal pain tolerance by resolved versus unresolved functional abdominal pain status. SBP values reflect values one standard deviation below (low SBP) and above (high SBP) the observed SBP mean. Fig. 1 View largeDownload slide Effect of resting systolic blood pressure (SBP) on thermal pain tolerance by resolved versus unresolved functional abdominal pain status. SBP values reflect values one standard deviation below (low SBP) and above (high SBP) the observed SBP mean. In contrast, the participant type × SBP interaction was nonsignificant in a regression in which thermal pain threshold was the dependent variable (R2 increment = 0.010, F change (1,143) = 1.50, p > .22). There was also no significant main effect of SBP on the thermal pain threshold outcome across the resolved and unresolved groups (Beta = 0.10, t(144) = 1.08, p > .28). Hierarchical multiple regression with the dynamic evoked pain outcome (temporal summation) as the dependent variable revealed a significant main effect for SBP, such that greater SBP was associated with lower temporal summation across the resolved and unresolved groups (Beta = −0.19, t(145) = −2.07, p < .05). For analyses of the temporal summation outcome, no significant participant type × SBP interaction was observed (R2 increment < 0.001, F change (1,144) = 0.03, p > .85). Possible Sex Differences Although limited by statistical power due to the small male subsample, the hierarchical regression analyses reported above were conducted again separately for males and females to address possible sex differences in BP-related hypoalgesia as a function of whether functional abdominal pain had resolved. In males, the participant type × SBP interaction for the temporal summation outcome was significant (R2 increment = 0.075, F change (1,55) = 4.434, p < .05). Simple-effect analyses indicated that this significant interaction in males was due to a nonsignificant trend for an inverse association between SBP and temporal summation in the resolved group (Beta = −0.283, t(38) = −1.725, p < .10) and a nonsignificant positive association in the unresolved group (Beta = 0.291, t(17) = 1.180, p > .25). For males, the participant type × SBP interaction was nonsignificant for both pain threshold (R2 increment = 0.016, F change (1,55) = 0.870, p > .35) and pain tolerance (R2 increment < 0.001, F change (1,55) = 0.015, p > .90). Parallel analyses in female participants revealed no significant participant type × SBP interaction for temporal summation (R2 increment = 0.020, F change (1,87) = 1.839, p > .17), pain threshold (R2 increment = 0.001, F change (1,87) = 0.051, p > .82), or pain tolerance (R2 increment = 0.022, F change (1,87) = 2.083, p > .15). Discussion BP-related hypoalgesia has been reliably demonstrated in normotensive pain-free individuals across the life span [3–5, 25, 35, 36]. Dysfunction in these BP-related hypoalgesic mechanisms has been evidenced in individuals experiencing chronic pain [14–18, 37]. To our knowledge, however, no prior study has adequately explored whether resolution of chronic pain is associated with the extent of BP-related hypoalgesia. To address this gap in the literature, we examined in adolescents and young adults who had suffered from chronic functional abdominal pain during childhood whether resolution versus nonresolution of this chronic pain condition was associated with different patterns of BP-related hypoalgesia. In addition, we explored the impact of chronic pain resolution not only in terms of responses to commonly reported static evoked pain measures but also regarding responses to dynamic evoked pain assessment (temporal summation) that are infrequently examined in relation to BP-linked hypoalgesia. We found significant correlations between SBP and both static and dynamic pain measures only in individuals in whom chronic pain had resolved. Specifically, SBP was significantly and positively associated with thermal pain threshold and tolerance and inversely associated with temporal summation in the pediatric-onset functional abdominal pain patients who were no longer experiencing chronic pain of any kind 9 years later. In contrast, significant BP-related hypoalgesic effects were not observed for any of these evoked pain outcomes in individuals with ongoing chronic functional abdominal pain. This pattern is consistent with the view that recovery from chronic pain might normalize BP-hypoalgesic function, although the interaction of resolution status with SBP was significant only for the thermal pain tolerance outcome. This latter finding indicates that pain tolerance was the evoked pain outcome most sensitive to associations between the resolution of chronic pain and extent of BP-related hypoalgesia. We had previously reported evidence for dysfunction of BP-related hypoalgesic mechanisms in young adults with a history of pediatric-onset functional abdominal pain [25]. In post-hoc analyses in this prior work using a smaller sample that only partially overlapped with this study, we reported that associations between resting SBP and pain threshold and tolerance outcomes did not differ significantly between subjects with ongoing functional abdominal pain (n = 35) and those in whom the condition had resolved (n = 60). A critical distinction between this prior work and this study should be noted, however. In this work, the total sample from which participants were drawn had increased substantially from what was available in 2010. As a result, this study permitted us to be more selective and provided a more defensible test of links between chronic pain resolution and BP-related hypoalgesia. Specifically, the larger total sample available for this study allowed us to contrast subjects with ongoing functional abdominal pain alone (with no other comorbid chronic pain; n = 51) versus those with resolved functional abdominal pain who had no other ongoing chronic pain complaints (n = 99). Thus, the current findings reflect not only a larger and statistically more powerful sample than the 2010 study but a sample entirely free of other comorbid chronic pain conditions that likely confounded results in our prior report. As a result, this article provides a higher quality test of hypotheses regarding the association of chronic pain resolution with extent of BP-related hypoalgesia than reported in our previous work [25]. The current findings suggest that BP-related hypoalgesic mechanisms may be more effective in individuals in whom chronic pain has resolved as compared to those in whom chronic pain has not resolved. Perhaps, individuals who recover from chronic pain not only have a cessation of ongoing pain but also experience a restoration of BP-related hypoalgesic mechanisms, which in turn may enhance their ability to adapt to subsequent acutely painful experiences. Alternatively, it is possible that chronic pain is more likely to resolve in individuals with more effective BP-related hypoalgesia. Because this study did not assess these hypoalgesic mechanisms at the time of initial functional abdominal pain diagnosis in childhood, it is not possible to ascertain which of these explanations is correct. Reasons for BP-related hypoalgesia being more effective in individuals in whom chronic pain has resolved are not yet known. Mechanisms involved in this hypoalgesia are believed to include endogenous opioidergic inhibition, alpha-2 adrenergic inhibition, and baroreflex sensitivity [10–13, 17, 18]. It has been hypothesized that reductions in BP-related hypoalgesia associated with chronic pain may derive from a combination of chronic pain-related decrements in these mechanisms, for example, impairments of endogenous inhibitory systems due to chronically excessive demands as chronic pain taxes homeostatic systems [9]. We can speculate that if these decrements are a result of chronic pain rather than a contributor, then resolution of chronic pain might help restore these systems, thereby normalizing BP-related hypoalgesia. This study design did not allow for determination of the causes of the less-effective BP-related hypoalgesia in individuals with ongoing chronic pain or the factors underlying apparent normalization of these adaptive systems once chronic pain resolves. Given evidence that chronic pain in adults may increase hypertension risk in part via mechanisms that also underlie BP-related hypoalgesia [37], replication of the current results in adults might imply that successful chronic pain management could help reduce comorbid hypertension risk in the chronic pain population. Measurement of both static (thermal pain threshold and tolerance) and dynamic (temporal summation) evoked pain outcomes allowed us to explore whether chronic pain-related alterations in BP-related hypoalgesia might derive from broad impairments in this BP-analgesic system or instead might be specifically associated with differences in BP-related inhibitory effects on ascending pain facilitation (i.e., temporal summation outcomes) like those that have been reported elsewhere [19]. Based on the absence of significant differences in links between resting BP and temporal summation as a function of chronic pain resolution status and the stronger resolution-related effects observed for the influence of resting BP on thermal pain tolerance, results seem to argue against central sensitization processes being a major contributor to alterations in BP-related hypoalgesic mechanism associated with chronic pain. Some prior work suggested that degree of BP-related hypoalgesia might differ by sex [36]; therefore, we explored the possibility that the relationship between chronic pain resolution and BP-related hypoalgesic mechanisms might differ in males and females. Indeed, analyses yielded some suggestive evidence for sex specificity. In males only, a significant participant type × SBP interaction was observed, specifically for temporal summation. Although the simple effects comprising this interaction did not reach statistical significance, results suggested that differences in associations between elevated SBP and reduced temporal summation across resolved and unresolved groups might be particularly notable among male FAP participants. The small size of the sample of males relative to females, however, limits the conclusions that can be made with regard to sex differences. To eliminate the possible confounding effects of suffering from comorbid chronic pain unrelated to functional abdominal pain, we excluded participants reporting any other forms of chronic pain from both groups. Nonetheless, this study has several potential limitations. First, there was a significant between-group difference in age, although the absolute difference in age between the resolved and unresolved groups was less than 2 years. Although it is not clear whether this difference was large enough to substantively affect the results, we do note that all hierarchical regression analyses statistically controlled for these age differences. Second, as noted previously, the sample size available did not have optimal statistical power for permitting definitive evaluations of any sex differences in the association of chronic pain resolution with extent of BP-related hypoalgesia. In summary, this study suggested better functioning in BP-related hypoalgesic mechanisms in young adults in whom childhood-onset, chronic functional abdominal pain had resolved compared with those in whom it had not resolved. Greater resting SBP was significantly linked to higher pain threshold, higher pain tolerance, and lower temporal summation in individuals in whom chronic pain had resolved, but not in those in whom it had not resolved. The magnitude of differences between resolved versus unresolved groups was largest for pain tolerance outcomes. The relation of chronic pain resolution status to associations between resting SBP and temporal summation (a hypothesized index of central sensitization) was more evident in males than in females. Future studies are needed to elucidate the mechanisms contributing to differing BP-related hypoalgesia patterns in those who recover versus fail to recover from chronic pain in childhood. Acknowledgements This research was supported by grants from the National Institutes of Health, including R01 HD23264 and R01 HD76983 (LSW), Vanderbilt Kennedy Center (P30 HD15052), Vanderbilt Digestive Disease Research Center (DK058404), and Vanderbilt CTSA (UL 1 RR024975); and a predoctoral fellowship (FPU13/03630) from the Spanish government (PDLC). Compliance with Ethical Standards Authors’ Statement of Conflict of Interest and Adherence to Ethical Standards Authors Pablo de la Coba, Stephen Bruehl, Judy Garber, Craig A. Smith, and Lynn S. Walker declare that they have no conflict of interest. All procedures, including the informed consent process, were conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Authors' Contributions P.C. contributed to conception and design of the study, conducted analyses, interpreted data, helped draft and revise the manuscript, and gave final approval of the submitted manuscript. S.B. contributed to conception and design of the study, assisted in conducting analyses and interpreting data, contributed to drafting and critically revising the manuscript, and approved the final version of the submitted manuscript. 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Journal

Annals of Behavioral Medicine – Oxford University Press

Published: Feb 14, 2018

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