The present study explored HPA-system activation in a sample of healthy children undergoing a series of experimental pain tasks. Although much research has focused on cortisol and stress in adults, no published study was identified that examined the relationship of cortisol and pain responses in healthy children and adolescents after laboratory pain-induction procedures.
As expected, saliva and blood cortisol samples correlated well in our sample, supporting the reliability of our assessments and the use of less-invasive saliva collection rather than blood sampling for cortisol assessment in studies of pain and stress responses in children. We also found that children’s age and time of day were significantly correlated with all cortisol readings (P < 0.001), and therefore these variables were included as covariates in the analyses.
The findings did not support our hypothesis that increased cortisol levels would be evident in response to the pain tasks. In fact, we found a different pattern. Cortisol levels were highest on arrival at the laboratory; these levels subsequently declined at SC1/BC1 after the pain tasks and did not change at SC2/BC2 (recovery, 20 minutes later). This pattern held true for the total sample and for boys and girls examined separately. These data suggest that children in the present study probably experienced the highest levels of stress before the baseline assessment (ie, before arriving at the laboratory). As the children became more familiar with the laboratory and pain procedures, the pain-inducing tasks were likely insufficient to produce an increase in cortisol beyond baseline. These findings were consistent with data from studies in adult populations,25–27
suggesting that the CPTs may be insufficient to produce a strong cortisol response unless a social/evaluative component (ie, being videotaped) is included. Our laboratory procedures lacked such a component. The most stressful activity may have been anticipation of the laboratory procedures, which may suggest that our study design was unable to capture a true baseline cortisol assessment. This explanation is consistent with previous findings that young boys and girls exhibited increased basal cortisol levels immediately before a stress task (as well as during the task), particularly in a laboratory compared with a naturalistic setting.28,29
Despite the fact that boys’ cortisol levels at baseline were ~0.18 nmol/mL and girls’ cortisol levels were ~0.13 nmol/mL, these differences were not significant, and no significant sex differences in cortisol levels were evident at any other assessment point (). Even though the literature on adults suggests that men have higher cortisol levels in response to stress compared with women,3
our data did not indicate similar sex differences in children. This finding is consistent with several previous studies in children that found no significant sex differences in cortisol responses to stress,12,30,31
supporting the possibility that the cortisol–stress relationship differs in children compared with adults.
Separate examination of the cortisol–laboratory pain response relationships by sex (controlling for age and time of day) suggested different sex-specific patterns. Higher cortisol levels were associated with lower pain reactivity (ie, increased pressure tolerance) among boys compared with girls. However, higher cortisol levels were related to a higher pain response (ie, increased cold intensity and unpleasantness) in girls than in boys (). These findings suggest that a greater pain response to the cold task was associated with increased cortisol responses in girls only, whereas a decreased pain response to the pressure task was related to increased cortisol responses in boys. These data from children mirror adult sex-differentiated cortisol findings. An experimental, laboratory-based study examining cortisol responses in 39 men and 37 women (age range, 19–29 years) before and after 2 trials of a cold water plunge test similar to the CPT found higher pain tolerance times during the second trial in men that were associated with a significantly larger increase in cortisol response, compared with the response in women (P
However, no significant sex differences in pain intensity or unpleasantness were found in either of the 2 trials. Another experimental investigation of sex differences in cortisol/pain responses to the CPT in 75 adults also found a negative association between pretask cortisol levels and pain perception in men only.6
Our data support these differential relationships between cortisol levels and pain in adult men and women and provide evidence that sex-specific stress–pain relationships may emerge early in development.
Another possibility is that sex-specific cortisol concentrations and pain relationships may differ in children and are more difficult to characterize than in adults. For example, one study found that among a sample of 102 children (43 girls, 59 boys) aged 5 years who participated in a stress task similar to the TSST-C, girls had significantly higher mean (SEM) cortisol levels in response to the stressor compared with boys (54.14 [30.28] vs 35.56 [19.84] μg/dL, respectively; P
In addition, the relationship of cortisol to behavioral and emotional problems was sex specific. Based on an interview conducted with each child, boys with higher cortisol levels had increased hyperactivity and impulsivity, and more internalizing problems compared with boys with lower cortisol levels. This relationship was not found in girls. However, girls with higher basal cortisol levels used significantly more positive emotions during a storytelling task compared with girls with lower cortisol levels (P
= 0.050). This relationship was not evident in boys. In another study, no significant sex differences in cortisol levels were found in response to a carbon dioxide inhalation challenge in a sample of 98 adolescents (51 boys, 47 girls; age range, 9–17 years).30
Similarly, in a sample of 31 healthy children (16 boys, 15 girls; age range, 9–15 years) who took the TSST-C, no sex differences were observed in either stress (as measured by heart rate) or cortisol responses. The data suggest complex sex-dependent relationships in young populations that may be different in children compared with adults.12,31
We also found sex differences in cortisol–pain relationships related to the method of cortisol assessment. Specifically, significant relationships were found with salivary cortisol in boys and with blood cortisol in girls (both, P
< 0.05). Although salivary and blood cortisol levels were highly correlated, this may suggest another sex-specific difference in cortisol response. To our knowledge, no other studies have examined cortisol differences across saliva and blood assessments in response to stress in children. A double-blind, counterbalanced study that examined salivary and blood cortisol concentrations in response to thermal and cold pain thresholds and tolerance in 26 adults (15 men, 11 women; age range, 18–40 years) found no significant sex-based differences between saliva and blood cortisol concentrations, despite women reporting significantly greater pain during a thermal heat task and the CPT (P
< 0.001 and P
< 0.01, respectively).33
Future studies should include multiple methods of cortisol assessment to continue exploring potential sex-based relationships between blood and salivary cortisol concentrations.
Findings from the present study highlighted sex differences in the cortisol–pain response relationship among children that resemble those found in adults. The current data support the hypothesis that HPA–stress set points may be established during childhood, and that there may be sex differences in these relationships. However, we found no evidence of consistently higher levels of cortisol in boys than in girls, as has been reported in adults. The study provides support for continued evaluation of sex differences in cortisol and pain across the developmental continuum, including longitudinally, and for evaluation of factors that are moderators and mediators of these relationships in males and females.
There are a number of limitations to the present study. Our data suggest we were unable to capture a true baseline cortisol reading before the pain tasks. SCb assessments were obtained as soon as subjects arrived at the laboratory, which did not permit sufficient habituation to the laboratory environment. The SCb reading was the highest compared with the posttask and recovery cortisol readings, indicating that the most significant stressor may have been anticipation of coming to the laboratory rather than the pain tasks. Although we could not obtain a true baseline reading, the data nonetheless suggest a similar pattern of cortisol response and recovery in boys and girls who are anticipating a stressor.
Possibly the study design (ie, presenting 3 pain tasks in 1 session) did not permit sufficient habituation of the central nervous system and pain pathways, thereby unintentionally creating a cumulative effect of increased pain sensitivity during the trials. However, we attempted to control for this possibility by counterbalancing the presentation of pain tasks, and we did not find any order effects during the laboratory session. Therefore, if a pattern of increased pain sensitivity emerged regardless of pain stimuli, we would have expected to see a nonspecific response across pain tasks. However, we found specific relationships for each task in boys and girls, suggesting robust findings.
Another potential limitation of the study was that the pain tasks and the stressor of the finger sticks for blood sampling may not have been sufficiently stressful to produce a reliable increase in cortisol activity. Despite self-reported data indicating that the pain tasks and finger sticks were at least moderately unpleasant and painful, the cortisol data generally did not support a strong HPA response to these tasks. As previously mentioned, it is possible that the children had become habituated to the laboratory and the procedures by the SC1/BC1 posttask assessment, and that the levels of cortisol decreased accordingly. Another explanation is that healthy children may not respond strongly to stress in the current procedures. In this healthy sample, cortisol represented only one aspect of the stress–pain response, and it is possible that a clinical population of children might exhibit a different pattern. In addition, although tasks (eg, the CPT) were relatively reliable predictors of stress responses, a number of studies have found only minimal to modest increases in cortisol after the CPT.3,26,34,35
Tasks that include a social-evaluative stress response are generally better predictors of HPA activity and stress, at least in adults.25,27
The pain tasks in the present study did not include a social stressor, as in the TSST-C.36
It is also possible that the timing of the salivary cortisol assessments did not capture the true peak in cortisol occurring 20 to 30 minutes after the first pain task.37
SC1 generally occurred 1 hour after SCb, a time lapse that may have obscured the initial rise in cortisol concentrations in response to the first pain task. However, given the high baseline values at SCb, it is unlikely that any subsequent stress task would have produced cortisol levels in excess of baseline. The biggest stressor may have been the anticipation of the procedures and the novelty inherent in arrival at the laboratory.
The nature of the study precluded obtaining a true random sample of participants, which prevents generalization of the study findings to all healthy children. Because of the study inclusion and exclusion criteria, these relationships may be different in the general population. In addition, sex-dependent relationships between pain responses and cortisol may differ in children with chronic pain.