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Cortisol is a key stress hormone that is implicated in a variety of physiological responses. Attenuated Cortisol Awakening Response (CAR) is associated with many negative health outcomes, but little research has investigated CAR and pain. The current study examines the association of CAR with experimental acute-pain ratings in healthy men and women. Attenuated CAR was related to greater pain intensity and unpleasantness ratings. Future research should examine this association across various pain populations.
The Cortisol-Awakening Response (CAR) is an important marker for psychological and metabolic health disturbances, yet it has received little emphasis in pain research (Prüssner et al., 1997; Lasikiewicz et al., 2008). In a normal CAR, cortisol concentrations reach their nadir during the early morning hours (Kirschbaum & Hellhammer, 1994) and the initial 30 to 45min post-awakening mark the steepest increase in cortisol (Edwards et al., 2001; Hucklebridge et al., 2002). In a flattened CAR there is little rise during the early morning hours, and this flattened response has been associated with various negative outcomes (discussed below). It has been suggested that a person’s CAR is consistent over days and even weeks making it a reliable biological marker of adrenocortical functioning (Prüssner et al., 1997; Lasikiewicz et al., 2008).
A flattened CAR has been associated with poorer general health, AIDS, cancer, post-traumatic stress disorder, chronic stress and burnout (Gaab et. al., 2005; Lasikiewicz, et. al., 2008). However, the existing literature on the association between CAR and pain is less well understood with findings ranging from negative (Gaab et al., 2005) to positive associations (Anderson et al., 2008) or none at all (e.g., see Khoromi et al., 2006). One study compared CAR in healthy controls and chronic Whiplash-Associated Disorder (WAD) patients who experienced chronic pain (Gaab et. al., 2005). The WAD patients showed a flattened CAR compared with the healthy controls, suggesting dysregulation of the cortisol diurnal rhythm and the HPA axis more broadly. Though the study did not explicitly examine the associations of CAR with pain, the authors suggested cortisol dysregulation could serve as a marker to understand chronic pain symptoms.
Dysregulation of cortisol is an indicator of chronic stress that can potentiate the experience of pain through its influence on the immune response (Kirschbaum & Hellhammer, 1994; Gaab et. al., 2005). In one previous study, reduced cortisol responses during acute pain were linked with greater pain perception during a laboratory pain task among healthy men; however, CAR was not measured in that study, which focused on cortisol reactivity to an acute pain task (al’ Absi, et al., 2002). The current study is the first to examine the association of naturally-occurring individual variability in CAR and acute pain responses among healthy men and women.
In the current study, healthy participants who exhibited a normal CAR during a day of diurnal rhythm salivary cortisol sampling were compared with participants who showed a flattened CAR on pain relevant outcomes.
Individuals (N = 80; 50% women ) of diverse ethnicities (20% African American, 29% Asian American/Pacific Islander, 45% Caucasian, 1% Native American, and 5% Other) with a mean age of 20 years, were recruited from the University and completed a screening battery to determine eligibility. Participant exclusion criteria included age younger than 18 or older than 45, ongoing chronic pain, diagnosed with hypertension or taking medication for blood pressure, circulatory disorders, history of cardiac events, history of metabolic disease or neuropathy, pregnancy, currently using prescription analgesics, tranquilizers, antidepressants, or other centrally acting agents, use of nicotine, use of prescription medication (e.g., corticosteroids), or diagnosed with a psychiatric disorder (e.g., depression) (Kirschbaum & Hellhammer, 1994). The protocol was approved by the University Institutional Review Board, and all participants gave written informed consent prior to the start of the study. Participants were compensated for their participation.
Participants attending the afternoon laboratory sessions listened to audio-taped instructions about the cold pressor task (CPT) and completed the CPT by immersing their dominant hand in 4°C (± 0.2°C) water for up to 5min. During the CPT, participants used a Numerical Rating Scale (NRS) to rate pain intensity and pain unpleasantness. At the end of the laboratory session participants were provided with detailed verbal and written instructions regarding home collection of saliva samples. Saliva samples were collected at home at seven time points. Research assistants guided participants in the selection of a suitable day for the collection of the saliva samples. Participants returned the saliva samples to the laboratory within one week of the laboratory session. Given concerns with adherence to home cortisol sampling (Thorn et al., 2006), participants completed a checklist indicating their adherence to the saliva collection procedures. For six participants (three from the normal CAR group and three from the flattened CAR group), adherence issues were reported (e.g., exercising or brushing their teeth); their inclusion or exclusion from analyses did not alter the findings, so all participants were retained in all analyses. The larger study from which the current data were drawn was a multi-factorial design whereby participants were randomly assigned via stratified sampling based on sex to one of four conditions. The conditions received different instructional sets about the CPT; however, no relevant manipulation effects were found on any relevant outcomes, and the total sample was used in the current study (N = 80).
The cold water acute pain stimulus was administered using a circulating cold water bath (ThermoNeslab RTE17, Portsmouth, NH) maintained at a temperature of 4°C. Participants completed one cold water immersion of the dominant hand. Participants were told they could withdraw their hand from the cold water at any time.
Seven salivary cortisol samples were obtained over the course of a single day as an approximation of each participant’s diurnal cortisol rhythm. At predetermined times (upon awakening, 15min, 30min, and 60min after awakening, and at 1100h, 1600h, and 2200h) participants placed a sterile cotton pad (Sarstedt) in their mouth for 2min 30s. Cortisol obtained in this way is not influenced by saliva flow rate and is in its unbound, biologically active state (Kirschbaum & Hellhammer, 1994). Samples were stored at -80°C until batch assayed using high sensitivity enzyme immunoassay kits (Salimentrics, State College, PA). To normalize the cortisol data a base 10 transformation was used.
Negative affect, a demonstrated correlate of worse pain outcomes (Sullivan et al., 2001), was assessed prior to pain testing using the Negative Affect subscale of the Positive and Negative Affect Schedule (PANAS; Watson et al., 1988). The PANAS has strong psychometric properties and the internal consistency of the PANAS negative affect scale was good in the current study (α = 0.83).
Participants completed a pain intensity rating and a pain unpleasantness rating using numerical rating scales (NRS) ranging from 0 (no pain) to 100 (most intense/unpleasant pain imaginable) immediately prior to removal of their hand from the cold water bath. Though these are common assessments of pain, they were highly correlated (r =.91, p <.0001), which limits their interpretation as unique indicators of pain. Pain tolerance was assessed as the total time in seconds of hand immersion in the cold water bath (300s maximum duration, which was unknown to participants).
Missing data on home cortisol saliva samples existed for 16 participants who did not differ from the full sample on sex, race, negative affect, pain tolerance, pain intensity, or pain unpleasantness and were excluded from analyses leaving a final sample N = 64 (53% female and 20 years old on average). Area under the curve with respect to increase (AUCI CAR) and ground (AUCG CAR) were calculated from CAR samples to capture the increase in salivary cortisol across the selected CAR time points (i.e., upon awakening and 15min, 30min, and 60min post awakening) (Pruessner et al., 2003). Following AUCI CAR calculation, a median split was used to create participant groups with either a normal or flattened CAR (the groups were significantly different; t (61) = 8.60, p <.001; see Figure 1).
The normal and flattened CAR groups were compared on negative affect, pain tolerance, AUCG CAR, and ratings of pain intensity and pain unpleasantness using t-tests. Sex, race, negative affect, pain tolerance, and total cortisol output were assessed for their association with the outcome variables pain intensity and pain unpleasantness for possible inclusion as covariates in the examination of the association of CAR group with pain intensity and unpleasantness ratings. No significant associations were found among these variables, and no covariates were included in the analyses.
The normal and flattened AUCI CAR groups did not differ in their report of negative affect, which may be the result of our healthy sample and a limited range (Range = 30), or pain tolerance (see Table 1). The normal AUCI CAR group was compared with the flattened AUCI CAR group on the total cortisol output during the CAR relevant cortisol sampling time points (AUCG CAR). AUCG CAR was significantly greater in the normal AUCI CAR group (M = 25.81, SD = 8.70) compared with the flattened AUCI CAR group (M = 11.74, SD = 6.77; t (61) = −7.15, p <.0001).
Two separate t-tests were used to test for AUCI CAR group differences in NRS pain intensity and pain unpleasantness ratings during the CPT. Participants in the flattened AUCI CAR group reported significantly greater pain intensity during the CPT (M = 80.56, SD = 14.74) compared with those who showed a normal AUCI CAR (M = 63.50, SD = 24.23; t (36) = 2.59, p =.014). Similarly, participants in the flattened AUCI CAR group also reported significantly greater pain unpleasantness during the CPT (M = 86.00; SD = 14.20) compared with those who showed a normal AUCI CAR (M = 70.25; SD = 22.09; t (36) = 2.58, p =.014).
To date the research on CAR and pain has shown mixed findings. This study adds to the field by showing an association of CAR with acute pain in healthy females and males. Specifically, attenuated CAR is associated with greater reported pain intensity and unpleasantness during an acute-pain task, which is consistent with other research showing attenuated CAR is associated with negative health outcomes (e.g., Gaab et. al., 2005; Lasikiewicz et. al., 2008). It is notable that we did not find associations of attenuated CAR with pain tolerance, which suggests that CAR may be particularly relevant to primarily subjective indicators of pain. In concert with the findings of at least one prospective study of persistent clinical pain (McBeth et al., 2007) these results suggest a flattened CAR may be part of a diathesis relating to dysregulation of the HPA axis, which places individuals at elevated risk for acute and chronic pain, although bidirectional associations are certainly possible. If this finding is replicated and extended, it would be of interest to examine whether interventions that “normalize” a flattened CAR also reduce the report of clinical pain.
The findings in this study are limited by several factors. Although attempts were made to ensure adherence to saliva collection procedures, the sample collection procedures may not have been adequately followed. Additionally, the saliva samples were obtained after the experimental pain session, which makes it possible their diurnal rhythms were different during the session; however, the diurnal rhythm of cortisol is typically stable over such a short span (i.e., less than one week) (Prüssner et al., 1997; Lasikiewicz et al., 2008). Finally, the statistical approach of taking the median split may create an arbitrary distinction between the groups; however, the groups were examined for, and demonstrated, statistical and meaningful distinction (see figure 1). No guidelines currently exist to appropriately define normal and dysregulated cortisol, so the use of such a statistical approach is warranted (e.g., see Lutgendorf et al., 2002).
This is the first study to examine CAR and acute pain ratings in healthy young men and women. Future researchers should attempt to extend this research into more diverse pain populations to determine whether CAR can serve as a marker for pain symptoms more broadly. Further it would also be helpful to examine the association of CAR across the development of chronic pain, paying particular attention to the quality of the pain report examined. Pain management is a critical issue for health professionals and identification of physiological markers could aid the development of targeted treatment plans.
We thank Ms. Kate Guilfoyle and Mr. Ray Richinelli who assisted with the data collection and project management.
Role of Funding Source
Funding for this study was provided by NIH Grant R21AT003250-01A1 (L. McGuire) and by a Special Research Initiative Support from the University (L. McGuire); the NIH nor the University had any further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication.
Conflict of Interest
All authors declare that they do not have any conflicts of interest.
ContributorsAuthors Mayes, McGuire, Edwards, and Haythornthwaite designed the study. Authors Mayes, McGuire, Page, Edwards, and Haythornthwaite were primary contributors to the writing of the manuscript. Author Page conducted salivary cortisol assays and Mayes undertook the statistical analyses. Author, Goodin, proof-read and edited the final draft of the manuscript. Author Mayes prepared the citations and references. All authors contributed to and have approved the final manuscript.
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