The principal aim of the present study was to examine whether pain catastrophizing is associated with aberrant adrenocortical responses to standardized pain testing, and among TMD patients in particular. We also were interested in whether TMD patients evidenced a stronger pattern of adrenocortical activity during painful stimulation than healthy controls and, lastly, whether TMD patients were characterized by generalized hyperalgesia. Although hypotheses were not fully supported, some noteworthy findings emerged.
Pain catastrophizing was not differentially associated with salivary cortisol profiles in the context of pain testing across TMD and healthy participants. However, we did observe that pain catastrophizing was associated with exaggerated cortisol responses to pain testing when collapsed across participant pain status. Put more appropriately in the context of the current study design, higher levels of catastrophizing were associated with a flattened or elevated morning cortisol profile in the context of acute pain. These are the first data to our knowledge that show a relationship between catastrophizing and salivary cortisol profiles in the context to standardized pain testing. These findings build on prior research suggesting that pain catastrophizing might yield maladaptive neurophysiological responses to painful experiences. For instance, positive associations between state
catastrophizing and interleukin-6 (IL-6) responses to highly similar laboratory-based quantitative sensory testing methods were recently noted19
. Moreover, catastrophizing has been associated with amplified activation of neural regions involved in the processing and regulation of affective elements of pain26,49
It is noteworthy that relations between catastrophizing and cortisol responses to pain emerged in patients and non-patients alike. These data suggest that pain catastrophizing may serve as a risk factor for the development of persistent pain as well as aggravate and/or maintain existing chronic pain via HPA pathways. Aberrant HPA axis integrity has been associated with worse post-operative pain outcomes, including pain severity23
. Moreover, hypo- and hypercortisolism have been associated with impaired inhibition of cellular pro-inflammatory cytokine proliferation47
. This is particularly noteworthy in light of the fact that inflammation enhances central sensitization12,39,53,63
, thereby putatively increasing vulnerability for transition from acute injury to a state of chronic, unremitting pain, or exacerbation and maintenance of existing pain. With emerging (albeit limited) evidence that pain catastrophizing may be related both
to exaggerated cortisol levels29 and
, it becomes possible to speculate that catastrophizing may be associated with a heightened state of glucocorticoid resistance at the cellular level, carrying the potential to account for associations between catastrophizing and clinical pain as well as pain-related functional outcomes, including sleep disturbance, fatigue and reduced activity levels21
. Although admittedly speculative, whether such processes play a role in shaping pain-related outcomes in association with catastrophizing represents a potentially intriguing direction for future research.
Pain catastrophizing was not associated with pressure and thermal pain threshold or cold pressor pain ratings, irrespective of pain status. Although it has been suggested that catastrophizing accounts for between 7 and 31% of variance in clinical pain52
, the literature has been rather mixed with respect to associations between pain catastrophizing and experimental pain sensitivity. It is important to keep in mind that all experiments must inform patients that they have control over any painful procedures through studies require informed consent. This likely limits the degree that catastrophizing processes ensue in a laboratory setting. Another intriguing idea is that trait-like assessments of pain catastrophizing may not capture responses to experimental pain testing as readily as state-like or situation-specific measures14,16,28
. Indeed, trait measures of pain catastrophizing instruct participants to base responses on recall of prior painful experiences which may have little or nothing to do with the type, duration or intensity of laboratory pain. Situation-specific measures catastrophizing heed participants to base their responses on the laboratory pain experience. This approach has the benefit of standardizing the referent and minimizing potential influence of recall bias37
. State assessments of catastrophizing appear to correlate more robustly with experimental pain than trait measures in healthy14,16,18,19,28
and in some clinical samples (Campbell CM, Manuscript Under Review), and have been linked to exaggerated IL-6 in the context of acute pain stimulation19
It is noteworthy that we obtained a significant association between pain catastrophizing and cortisol responses to pain despite observing no association between catastrophizing and experimental pain sensitivity, or between any index of pain sensitivity and cortisol. It is possible that we failed to assess a crucial dimension of the catastrophizing-pain interface, such as pain-evoked distress, or hypervigilance to pain-related sensory and affective information61
. For instance, it is possible that the sensory pain experience per se does not drive the catastrophizingcortisol association. Instead, it might be the affective constituent of pain that is exaggerated for pain catastrophizers41
, thereby triggering a more robust stress response. Unfortunately, our data cannot address this hypothesis. We also failed to observe an association between our indexes of pain sensitivity and cortisol. This finding is not inconsistent with prior research. For instance, a recent study reported correlations between “state” catastrophizing and IL-6 responses to acute pain stimulation in the absence of an association between pain itself and IL-619
. Moreover, two studies6,22
that examined IL-6 levels post-operatively failed to show an association between IL-6 levels and self-reported levels of post-operative pain; despite a disassociation between IL-6 and pain, these studies observed robust increases in IL-6 following surgery. It seems clear that an important area for future research is to isolate possible mechanisms by which pain and pain catastrophizing shape neurophysiological responses to pain. Thus far, it appears that a conceptual model linking catastrophizing to exaggerated neurophysiological responses to pain via increased pain per se is not a viable one.
TMD patients had lower pressure pain thresholds at the affected anatomical site than healthy controls. This finding enhances confidence that TMD diagnoses in the present study were accurate. However, evidence for generalized hyperalgesia among TMD participants was not observed, which is at odds with some prior investigations but consistent with others48
. A plethora of factors appear to moderate pain sensitivity, and not taking them into consideration may have diminished our ability to detect generalized hyperalgesia in TMD patients, which is a highly heterogeneous disorder. One such genetic factor that highlights the heterogeneity in TMD are the single nucleotide polymorphisms (SNP) of the catechol-o-methyltransferase (COMT) genotype. A “pain sensitive” haplotype of this SNP enhances pain sensitivity9,10,66
, for exceptions, see 32,33
and has been identified as a likely genetic determinant of transition to TMD8,10
. George and colleagues24,25
have shown that a pain sensitive COMT diplotype moderate relations between catastrophizing and clinical pain report.
Recent work by our group suggests that sleep disorders are another important and prevalent moderator of alterations in generalized pain sensitivity in TMD50
. We found that the diagnosis of primary insomnia (26% of TMD sample) was associated with generalized hyperalgesia in TMD, whereas sleep apnea diagnosis (28% of TMD sample) was associated with generalized hypoalgesia. We also found that reduced sleep efficiency is associated with impaired pain inhibitory function in TMD20
. Failing to take into consideration potential moderating factors might have restricted our power to detect between-groups differences in responses to pain testing.
Some study limitations warrant mention. First, we conducted pain testing and obtained salivary samples for cortisol measurement in the morning during the diurnal cortisol decline. Although this may have limited our ability to detect pain status differences in salivary cortisol responses to pain testing, we nonetheless detected a significant association between pain catastrophizing and salivary cortisol responses. This may speak to the robust effect of catastrophizing on HPA responses to pain. Conversely, it is possible that the effect observed in the present investigation can be attributable to Type I error. Interestingly, a recent study revealed that absolute pre-stress levels
of salivary cortisol are greater in the morning than in the afternoon or evening, where as salivary cortisol responsiveness
to psychological stress does not appear to differ across morning and afternoon sessions35
. Nonetheless, these findings require replication and extension.
Second, and not uncommonly, we did not include a no-pain control condition. Hence, associations between catastrophizing and salivary cortisol profiles might have had little to do with pain testing, instead representing an association with some “third” variable. However, it is well-recognized that cold pressor pain stimulates HPA response at both pituitary and adrenocortical levels2
. Moreover, at present, there exists little empirical or theoretical reason to posit that catastrophizing would be associated with tonic exaggerations in HPA activity that are independent of pain exposure, particularly among healthy pain-free participants. Third, we do not have data that attest to the mechanism(s) by which pain catastrophizing is associated with adrenocortical activity. Even more problematic is that our cross-sectional approach does not allow for causal statements. The process of catastrophizing during pain exposure might enhance the subjective experience of pain, thereby affecting neurophysiological processes. Conversely, exaggerated neurophysiological responses to pain might cause an individual to catastrophize. Potential “third” variable mediation of catastrophizing and exaggerated HPA responses to pain also cannot be ruled out. Lastly, we did not include measures of other negative pain cognitive process variables, such as fear of pain or pain anxiety. Hence, we can only tentatively speak to the specificity of the findings with respect to catastrophizing.
These limitations notwithstanding, these findings suggest an intriguing association between pain catastrophizing and exaggerated HPA activity in the context of acute standardized laboratory pain testing. These data point to a potential neurophysiological pathway by which catastrophizing may confer risk not only for the maintenance and/or exacerbation of existing TMD pain, but for the development or onset of persistent pain. Bridging these findings with those indicating exaggerated inflammation associated with catastrophizing19
may yield novel insights into the processes by which pain catastrophizing shapes pain-related outcomes. Clinically, it has been well-documented that reductions in pain catastrophizing in the context of cognitive-behavioral therapy for TMD play a critical role in shaping immediate and longer-term outcomes58–60
. It is a distinct possibility that cognitive-behavioral interventions not only affect cognitive processes that an individual brings to bear on painful encounters, but restores HPA function and crosstalk between neuroendocrine and immune pathways4
. The study of the neurophysiological basis of pain catastrophizing is in its infancy, but these and other findings suggest that this promises to be an exciting and important area of investigation in the coming years.