Acute Jaw: Cortisol 1
Journal of Applied Biobehavioral Research, in press
DECREASES IN CORTISOL VARIABILITY BETWEEN TREATED
AND UNTREATED JAW PAIN PATIENTS*
Robert J. Gatchel, Ph.D. * * * *
J.P. Garofalo, Ph.D.***
Richard C. Robinson, Ph.D.**
* Supported in part by Grant Nos. 2RO 1 DE 10713, K05 MH0 1107 and 3RO 1 MH46402 by the National Institutes of Health. Correspondence concerning this article should be addressed to Robert J. Gatchel, PhD, The University of Texas at Arlington, P.O. Box 19528, Arlington, Texas 76019
**Baylor University Medical Center, Baylor Centers for Pain Management; Clinical Assistant Professor, Department of Psychology, The University of Texas Southwestern Medical Center at Dallas ***Assistant Professor, University of Washington, Pullman Campus
****Professor and Department Chair, Department of Psychology, The University of Texas at Arlington
RUNNING HEAD: ACUTE JAW: CORTISOL
Acute Jaw: Cortisol 2
ABSTRACT
Background: Endogenous cortisol levels are believed to be a valid biological marker of stress. The primary study aim centered on evaluating the impact of treatment on cortisol levels in patients at high-risk for progressing from acute to chronic jaw-related pain. Method: Twenty-five patients (21 women and 4 men) with complaints of jaw pain or facial discomfort for less than 6 months, with those of high-risk status assigned to a biobehavioral intervention, and those of lower-risk status assigned to a standard care condition. Baseline data, which included completing questionnaires about their pain and providing a saliva sample, were collected every day for the first two weeks of the study, and then three times/week for nine weeks. Results: A 2 x 2 factorial ANOVA revealed that cortisol levels significantly increased over time in both conditions, F (1, 429) = 6.614; p = .0 10 and an interaction existed between treatment condition and time of cortisol collection in terms of cortisol variability, F (1,429) = 14.673; p < .00 1. The treatment condition demonstrated a significant decrease in cortisol variability (p < .043), while the non-treatment condition demonstrated a significant increase in cortisol variability (p < .004). Conclusions: Together, these findings underscore the potential influence of Hypothalamic-Pituitary-Adrenal axis
(HPA) activity in chronic pain. In particular, greater dysregulation of the HPA axis was observed in the nontreatment group, suggesting that cortisol may represent a biological substrate that influences the persistence of pain from the acute stage to the chronic stage.
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Decreases in Cortisol Variability between Treated and Untreated Jaw Pain Patients
The most common reason people in the United States seek medical or dental care is due to pain (Gremillion, 2000; Edwards et al., 2004; Sarlani et al., 2005). It has been estimated that approximately more than 20% of the U.S. population experience orofacial pain on more than one occasion in a six-month period, and that 65-85% experience some temporomandibular disorder (TMD) symptoms during their lives (Dworkin et al., 1990; Kapur, Kamel, & Herlich, 2003; Lipton, Ship, & Larach-Robinson, 1993). Further, 5-12% of the population progress from acute to chronic TMD symptoms (Duckro, Tait, Margolis, & Deshields, 1990; Dworkin et al., 1990; Gatchel, 1996;Lipton et al., 1993; Svensson & Graven-Nielsen, 2001; Gatchel, 1996). Although prior efforts to identify risk factors for developing chronic pain problems have underscored both psychological and biomedical factors, little attention has been devoted towards endocrinological mechanisms. This dearth in the literature is particularly surprising in view of the fact that stress, and the negative cognitions and/or emotions often intertwined with the pain experience, can activate the hypothalamic-pituitary-adrenal (HPA) axis.
TMD is characterized by a combination of physical, functional, and psychosocial adverse symptoms in the orofacial region (Carlson et al., 1993; Dworkin et al., 1990; Gatchel, 2002; Manfredini et al., 2004; Schmitter et al., 2005; Suvinen & Reade, 1995). Many factors including physical structures in the mouth, musculature, and psychosocial functioning appear to contribute to TMD (Baba et al, 2005; Carlson et al., 1993; Gremillion, 2000; Laan, Duinkerke, Luteijn, & Poel, 1988; Macfarlane, Kincey, & Worthington, 2002). Oakley and colleagues (1993) reviewed the need for considering psychosocial factors as a contributing factor in TMD patients who do not respond to traditional medical and dental approaches to pain management. Together, these studies have shown that not only should stress be considered to be a pivotal mechanism in the initiation of TMD symptoms, but that it may also play a role in its maintenance.
The focus of prior research has centered on the observed relationship between stress-induced muscular activity and pain symptoms (Keefe & Dolan, 1988; Yemm, 1985). More recently, Melzack
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(Melzack, 1996, 1999, 2001) proposed the neuromatrix theory of pain that conceptualizes chronic pain as caused by neural mechanisms of sensory transmission, genetic contributions, and neural-hormonal mechanisms of stress. This model postulates that pain presents not only as a purely perceptual phenomenon but, instead, as a source of disruption to the entire homeostatic regulation system of the organism. Assessment and treatment approaches of pain will improve as long as the role of the psychophysiological stress system in pain processes significantly is recognized. Indeed, chronic pain presents as a stressor capable of taxing the stress-regulation systems. Prolonged dysregulation of these systems will ultimately lead to a wearing of muscle, bone, and neural tissue that in turn, will cause more pain and produce a vicious cycle of pain-stress-reactivity.
One stress-related index that Melzack suggests to be important in the above pain-stress cycle is cortisol. Specifically, along with the activation of the sympathetic nervous system, cortisol establishes the foundation for the stress response. Although increased cortisol secretion is considered to be an adaptive response mechanism when stressed (for purposes of energy mobilization), prolonged secretion can lead to a wide-range of negative effects (e.g., muscle atrophy, impairment of tissue repair, immunosuppression, etc. (Gaab et al., 2005; Goldman et al., 2005; McEwen, 2005; Sapolsky, 1996; Turner-Cobb, 2005). Melzack suggests that cortisol serves as a good marker of the degree that stress influences the development of chronic pain. This aspect of his theory was evaluated in the present investigation.
Cortisol can be easily and reliably obtained in a noninvasive manner in human subjects. Pruessner and colleagues (Pruessner et al., 1997) reported three independent studies demonstrating that cortisol level after morning awakening, assessed by sampling saliva, is a reliable biological marker for adrenocortical activity. Other systematic research studies have shown salivary cortisol to provide an accurate index of free plasma cortisol (for a review, refer to Kirschbaum & Helhammer, (Kirschbaum & Hellhammer, 1994). Further, McEwen (McEwen, 1998; 2005) reviewed the detrimental impact of the accommodation to stress that may result in dysregulation of the cortisol system. Repeated or ongoing
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stressors are hypothesized to result in an impaired ability to maintain homeostasis, leading to dysregulation.
The primary study questions addressed bore on the role of cortisol as a potential index of psychophysiological stress modification in response to a biobehavioral intervention offered to patients with jaw pain. Specifically, it was hypothesized that cortisol dysregulation would be associated with chronic pain. If such dysregulation does exist, it was also hypothesized that those jaw pain patients receiving a biobehavioral intervention with a strong stress-management would exhibit reduced dysregulation in the HPA axis relative to those patients not receiving such treatment.
METHOD
Participants
A sample of 25 patients (21 women and 4 males) was drawn from a larger cohort of TMD  patients with complaints of jaw and/or facial discomfort for less than six months. Assignment was based  on risk status as determined by a statistical algorithm derived from a relative operating characteristic  (ROC) curve analysis (developed on the large cohort of patients) to identify those patients at greater risk for developing chronicity (Epker, Gatchel, & Ellis, 1999). Twenty-five patients (21 women and 4 men) with complaints of jaw pain or facial discomfort for less than 6 months, with assignment to a biobehavioral intervention based on risk-status: Once the algorithm was applied, those of high risk status for chronic pain were assigned to the treatment condition and those of low risk status were assigned to a standard care condition, where they were referred back to their dentist or sought treatment on their own. The two groups were carefully matched for demographic variables (e.g., age, gender, race, marital status, education) and time since original onset of TMD. Data cortisol samples were collected every day for the first two weeks of the study, and then three times/week for nine weeks. General dentists and oral surgeons in a major metropolitan city referred participants to the study. In addition, flyers and advertising were placed at local universities and local newspapers to recruit subjects. Potential participants were excluded if they had some other chronic, significant pain-exacerbating physical condition (e.g., cancer or
Acute Jaw: Cortisol 6
fi bromyalgia), or a past history of jaw pain.
Design
Applying a quasi-experimental design, the primary study aim sought to characterize
potential cortisol dysregulation among acute pain patients, particularly those at greater risk for their pain to persist until deemed chronic. In addition, using cortisol dysregulation as a marker of
stress, the study sought to examine whether the introduction of an early intervention would reduce cortisol dysregulation among patients at high risk for chronic pain compared to lower risk
patients undergoing standard care. Those patients assigned to this non-intervention condition were not denied anything they might have normally received. Repeated-measures analyses of variance of the cortisol levels sampled during the one-year follow-up period will be conducted to test these hypotheses.
Procedure
Based on methodology recommended by Schulz and colleagues (1998), free cortisol levels were analyzed by collecting saliva samples after awakening and 20 minutes later by placing a cotton salivette in their mouth. Cortisol data were collected every day for the first two weeks of the study, and then three times a week for the remainder of the study. For the purpose of this article, only the first morning sample was analyzed. Each sample was analyzed twice, and the average of the two cortisol levels was computed and expressed as ^g/dl. Further, the mean and standard deviation of each participant’s cortisol level were calculated and transformed into T-scores to allow for comparison of change from each individual’s personal cortisol baseline. The personal baseline for this study was the person’s average cortisol over the course of the study period. Transformation of the cortisol level into T-scores allowed us to conduct comparisons both within and between subjects. For instance, an individual on day 12 of the study may
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have had a cortisol level that was one standard deviation above their baseline and another individual may have had a cortisol level that was two standard deviations above their baseline.
It should be noted that it was recognized that patients might seek out and receive a variety of treatments, including occlusal splints, TENS, muscle relaxants, analgesics, sedatives, anesthetic injections into muscles/joints, jaw manipulations, and a host of others. The compliance and duration of use of many of these treatments is difficult to quantify, and thereby become uncontrolled variables. Due to their episodic nature, we are continuing to collect these data and evaluate to what extent their presence might influence cortisol levels.
Materials
Graded Classification Scale of Pain Dysfunction. Efforts to identify acute pain patients was based on the graded classification of pin dysfunction. Von Korff and colleagues (Von Korff, Ormel, Keefe, & Dworkin, 1992) have found this Axis II scale of the RD C/TMD to have good concurrent and predictive validity in primary-care pain patients. There are four major indices used: Changes in the actual classification grade from pretreatment to follow-up (Grade 0-IV); changes in pain intensity; changes in pain disability; changes in disability days.
Intervention. The early intervention used in this project was the biobehavioral treatment-intervention protocol found to contribute to the most effective one-year outcomes in past studies (Gardea, 1998)—the combined relaxation-biofeedback and cognitive-behavioral skills training (CBST) group. Indeed, in a recent comprehensive review and meta-analysis of randomized controlled trials of cognitive-behavior therapy, Morley, Eccleston and Williams (Morley, Eccleston, & Williams, 1999) concluded that interventions based on the principles of cognitive behavior therapy produce significant improvement in various domains of pain (such as pain experience, mood/affect, coping, functioning, etc.) in patients with pain, including TMD . Patients were reminded during each session of the importance of maintaining
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treatment compliance and avoiding alternative treatments during the course of the study. The major treatment components administered were as follows:
1) The cognitive-behavioral therapy (CBT) component followed the detailed intervention manual developed and successfully employed in past projects. This early intervention was further “tailored” to each patient based on gender, personality, and level of depression. Patients were informed that persistent medical and dental problems are associated with stress, which can lead to significant emotional reactions such as anxiety and depression.
2) The relaxation-biofeedback treatment protocol followed a format developed by the Gatchel (Gatchel, 2000) (who specializes in biofeedback and stress-management techniques) in the treatment of TMD patients.
3) Clinical psychologists with a background in cognitive-behavioral treatment techniques served as the therapists. In order to maintain the quality and integrity of the intervention, the therapists were routinely monitored by independent consultants who initially trained the therapists and subsequently monitored their performance by reviewing randomly selected cases that were taped. The therapists also met with an experienced consulting therapist on a weekly basis to receive feedback and receive any required booster training.
RESULTS
Primary hypotheses of this research focused on cortisol amounts, cortisol variability, as well as self-reports of pain severity. Inferential statistical analyses were used to test the relationships between cortisol and pain reports (on a 10-point Visual Analog Scale). Data analyses for both hypotheses involved several steps. In terms of the first hypothesis, simple Pearson correlations were calculated separately for the treatment and non-treatment groups. For the treatment group, an association between pain and mean cortisol levels was observed (r = .31 1, p <.001); however, a significant relationship was not observed between these two variables the nontreatment group (r = -.048, p = .272).
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Further, the first two weeks of samples from each patient were compared to the last two weeks of samples from each patient, and average mean cortisol, pain rating, cortisol variability and pain variability were compared. Further, a week for winter holidays during the month of December was excluded from analyses as the stress associated with this holiday appeared to increase cortisol variability. As can be seen in Table 1, no significant differences existed with regard to age, gender, race, marital status or education level.
INSERT TABLE 1 ABOUT HERE
In addressing the second hypothesis, a 2 x 2 factorial ANOVA was performed for each of the main cortisol endpoints (Table 2). Mean cortisol level significantly increased in both the treatment and non-treatment groups, F (1,429) = 6.614; p = .0 10, and there was a significant difference between the treatment conditions, F (1,429) = 6.633; p = .010. Of note, analyses revealed that a significant interaction between treatment condition and time of cortisol collection existed with regard to cortisol variability, F (1,429) = 14.673; p < .001. Further, two-tailed, paired-samples tests revealed that subjects in the treatment condition demonstrated a significant decrease in cortisol variability (p < .043), and subjects in the non-treatment condition demonstrated a significant increase in cortisol variability (p = .004; see Figure 1). Effect size was also calculated, and a large effect size was found with regard to cortisol variability (ES = .84).
INSERT TABLE 2 & FIGURE 1 ABOUT HERE
For self-reported pain ratings data, which paralleled that of the cortisol data, there was a
significant difference found between treatment groups, F (1,432) = 35.759, p < .001, as well as over time
of cortisol collection, F (1,432) = 5.437, p = .02. Moreover, there were significant treatment differences
Acute Jaw: Cortisol 10
for pain variability, F (1,432) = 35.759, p < .001, and across cortisol collection times, F (1,432) = 21.249, p = .03 1.
DISCUSSION
The data revealed support for the study hypotheses. Consistent with prior studies that have found an association between psychiatric and medical illness and cortisol dysregulation, the results revealed that such an association is present in a jaw pain population. We might speculate that such dysregulation plays a role in the pathophysiology of chronic pain as evidenced by the observed large variance in cortisol dysregulation among the pain patients. These findings not only are consistent with the results of a recent empirical investigation (Yoshihara et al., 2005), but that our findings build on these results. Specifically, Yoshihara and colleagues observed both increased cortisol concentrations as well as a slower rate of recovery of cortisol levels among myofacial pain patients compared to health controls. Our findings extend these results to suggest that dysregulation of the HPA system exists, and likely serves as a risk factor for chronic pain. While it remains unclear as to whether this dysregulation is initiating the prolonged pain response or if is a consequence of the pain experience, these two investigations argue for prospective studies to address this question.
One potential explanation is that excessive levels of endogenous cortisol characterize the acute pain stage, and that subsequent dysregulation of the HPA axis might facilitate pain nociception until it is deemed to be chronic. In terms of the study hypothesis, the absolute differences from baseline were calculated for each sample and compared among individuals. Data revealed decreased cortisol variability in participants within the treatment group, and an increase in cortisol variability found in the participants in the non-treatment group. To the best of our knowledge, this study represents the first systematic effort in a pain population to demonstrate the effectiveness of a multidimensional intervention in impacting an endocrine marker. In addition, this study revealed that patients undergoing treatment have cortisol levels that are closer to their baseline toward the end of treatment than toward the beginning of treatment. This finding implies that the dysregulation of the HPA axis is amenable to intervention.
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One of the strengths of the current study was the focus on the pattern of endogenous cortisol rather than its amount. The research design facilitated this finding by introducing the opportunity to collect multiple samples of salivary cortisol . Cortisol dysregulation has not been clearly operationalized and is difficult to study as significant inter-individual variability exists. By calculating an individual’s personal cortisol baseline and transforming the mean cortisol levels to T-scores, inter-individual comparisons become possible. Inconsistency and erratic functions of the H PA axis support the notion that its dysregulation contributes to the pain experience. Of course, it should be noted that the analysis of cortisol variability posed a particular challenge, and transforming the difference from baseline to T-scores undoubtedly lowered the true variability. With regard to gender, consideration was given to excluding all male subjects. However, the main endpoint, cortisol variability after treatment, would not have been significantly impacted with the inclusion of male subjects, and a significant difference in the number of male subjects in the treatment conditions did not exist. Although samples were compared from the first two weeks of the study to the last two weeks, more samples were collected during the first two week compared to the last. Future studies would benefit by adding measures of diurnal variation at set times before, during and after treatment.
There are a few limitations that need to be considered prior to extending the study results to other populations. First, the study employed a quasi-experimental condition in which assignment to the experimental and control condition was based on risk-status for chronic pain. The inclusion of a low-risk status group was essential to the research design for the investigators sought to determine whether dysregulation of the H PA axis was greater in a higher risk subset of TMD patients. If such dysregulation does serve as a risk for factor in rendering pain more chronic, then an optimal point of comparison is not to a healthy control group, but a clinical population that only differ in terms of their risk for chronic pain. As part of a larger-scale study, we are currently in the process of identifying acute TMD patients identified as being at high-risk for their symptoms to become chronic, and will be randomly assigned to either the early-intervention group or a standard-care group.
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In addition, as we noted in our methodology section, we are continuing to collect data regarding concomitant use of alternative treatments in either experimental condition. It is well-established that other factors can influence cortisol levels and variation. Hence, our findings should be interpreted with caution until we have determined to what extent treatment outside of the biobehavioral intervention program influenced our primary endpoints.
In conclusion, the study results may provide leads for future studies of the role of cortisol dysregulation in pain populations both in terms of assessment and intervention. Identifying a subset of acute pain patients with cortisol dysregulation, which is either maintained or exacerbated by psychological mechanisms, introduces a unique biomarker for chronicity that ultimately will guide the delivery of interventions, as well as their justification to third-party payers. These findings also underscore the need for a strong psychoeducational component directed at improving stress-management in acute pain patients at risk for chronicity.
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