Childhood Maltreatment and Diurnal Cortisol Patterns

Childhood Maltreatment and Diurnal Cortisol Patterns in Women With Chronic Pain NANCY A. NICOLSON, PHD, MARY C. DAVIS, PHD, DENISE KRUSZEWSKI, MA,

AND

ALEX J. ZAUTRA, PHD

Objective: To assess whether alleged childhood maltreatment is associated with daily cortisol secretion in women with chronic pain. Method: Women with fibromyalgia (FM group, n ⫽ 35) or with osteoarthritis only (OA group, n ⫽ 35) completed diaries and collected three saliva samples daily for 30 days, with compliance monitored electronically. Childhood abuse and neglect were assessed by self-report (Childhood Trauma Questionnaire-short form [CTQ-sf]). Multilevel regression analyses estimated associations between maltreatment and diurnal cortisol levels and slopes, controlling for depressive symptoms, posttraumatic stress disorder (PTSD), and daily experience variables. Results: Women reporting more severe childhood maltreatment had higher cortisol throughout the day. The estimated effect of CTQ on log cortisol (␤ ⫽ 0.007, p ⫽ .001) represents a 0.7% increase in raw cortisol level for every unit increase in maltreatment score, which ranged from 25 (no maltreatment) to 106 in this sample. Although different forms of maltreatment were interrelated, emotional and sexual abuse were most closely linked to cortisol levels. Fibromyalgia and osteoarthritis groups showed similar secretory patterns, and maltreatment was associated with elevated cortisol in both. Although maltreatment was related to symptoms of depression, PTSD, and averaged daily reports of positive and negative affect, none of these variables mediated the link between maltreatment and cortisol. Conclusions: In women with chronic pain, self-reported childhood maltreatment was associated with higher diurnal cortisol levels. These results add to the evidence that abuse in childhood can induce long-term changes in hypothalamic-pituitary-adrenocortical activity. They further underscore the importance of evaluating childhood maltreatment in fibromyalgia and other chronic pain conditions. Key words: salivary cortisol, childhood maltreatment, abuse, chronic pain, fibromyalgia, osteoarthritis. CTQ-sf ⫽ Childhood Trauma Questionnaire-short form; HPA ⫽ hypothalamic-pituitary-adrenocortical; PTSD ⫽ posttraumatic stress disorder.

INTRODUCTION substantial body of research (1) has examined whether maltreatment in childhood contributes to the development of adult pain syndromes. The hypothesis that childhood trauma predisposes individuals to develop pain conditions has been especially prominent for syndromes that involve pain of unknown origin together with psychological complaints. One such syndrome is fibromyalgia, in which widespread musculoskeletal pain is often accompanied by fatigue, sleep disturbance, and affective symptoms. Of note, fibromyalgia is six to nine times more prevalent in women than in men (2). A history of childhood trauma is common among individuals with fibromyalgia, with an estimated 30% to 55% of patients reporting childhood sexual and/or physical abuse (3–7). Even compared with women with other chronic pain conditions, women with fibromyalgia are more likely to report a history of childhood abuse (5,8,9) and show a stronger association of trauma severity with adult functional disability and distress (4,10 –12). One mechanism potentially mediating the relationship between childhood trauma and fibromyalgia in adulthood is dysregulation of the hypothalamic-pituitary-adrenocortical

A

From the Department of Psychiatry and Neuropsychology (N.A.N.), School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; and the Department of Psychology (M.C.D., D.K., A.J.Z.), Arizona State University, Tempe, Arizona. Address correspondence and reprint requests to Nancy Nicolson, PhD, Department of Psychiatry and Neuropsychology, Maastricht University, P.O Box 616, 6200MD Maastricht, Netherlands. E-mail: [email protected] Received for publication July 9, 2008; revision received December 17, 2009. This study was supported, in part, by Grant RO1 AR046034 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (A.J.Z., Principal Investigator). DOI: 10.1097/PSY.0b013e3181d9a104 Psychosomatic Medicine 72:471– 480 (2010) 0033-3174/10/7205-0471 Copyright © 2010 by the American Psychosomatic Society

(HPA) axis (13). Both childhood trauma and fibromyalgia have been associated with abnormalities in HPA activity. Studies (14) of maltreated children, for example, reported both increased and decreased levels of cortisol; the degree of neuroendocrine dysregulation seemed to differ by sex and age at exposure, among other factors. Diurnal cortisol profiles, which normally display a pronounced decline from early morning until bedtime, are sometimes flattened in abused and neglected children (15). Current symptoms of posttraumatic stress disorder (PTSD), internalizing and externalizing symptoms, and ongoing adversity may influence the degree and direction of HPA axis abnormalities (16). Adults allegedly abused as children may display low basal cortisol levels, whereas cortisol reactivity to psychosocial stressors may be enhanced (16,17). Childhood trauma has been associated with elevated cortisol levels in other studies (18). As in children, whether basal cortisol levels are high or low over the day seems to depend on characteristics of the stressor as well as the nature and severity of current psychiatric symptoms (19). Findings concerning HPA function in fibromyalgia are complex and inconsistent. Studies that obtained repeated blood samples over 24 hours revealed lower (20) or normal (21,22) basal cortisol levels. The circadian secretory pattern seemed normal in some studies (21,22), whereas others found undisturbed peak cortisol levels in the morning but relatively high evening levels (20,23,24), without the usual nocturnal quiescent period in half of the fibromyalgia patients (25). Low morning plasma cortisol levels have also been observed, with the lowest levels in patients with more severe sleep disturbance, fatigue, and depression (26). Compared with healthy controls, fibromyalgia patients displayed elevated salivary cortisol throughout the day in one study (27), but normal levels in another (28). Twenty-four-hour urinary free cortisol levels are reported to be low (20,23) or normal (29,30). Psychosocial and dynamic challenge tests reveal normal or reduced cortisol reactivity to applied stressors (31,32). Diverse findings have been summarized by some researchers 471

N. A. NICOLSON et al. (25) as evidence of hypercortisolism and HPA hyperactivity; in contrast, others (33,34) described hypocortisolism as a general feature of the disorder. Although there is no consensus about the nature and extent of HPA axis abnormalities in fibromyalgia (35), researchers (25,26,31) emphasized the importance of evaluating comorbid disorders (e.g., chronic fatigue syndrome, depression, PTSD, sleep disturbances) as well as traumatic experiences to clarify the heterogeneity of findings. Two investigations have explored the links between childhood trauma and cortisol levels in fibromyalgia. McLean and colleagues (28) examined the relationship between earlier sexual and/or physical abuse and salivary cortisol levels in 16 women with fibromyalgia. A positive abuse history was associated with lower salivary cortisol levels on awakening and a flatter diurnal slope. Weissbecker et al. (7), assessing the association between self-reported childhood maltreatment and salivary cortisol in a larger sample, found that women reporting higher levels of physical abuse displayed a flatter diurnal decline in cortisol secretion, and both physical and sexual abuse were associated with lower cortisol levels at awakening and greater cortisol increases in the 45 minutes thereafter. In addition, emotional abuse was related to higher evening cortisol. The associations between childhood maltreatment and cortisol levels were especially pronounced among women who were not depressed and were sustained in models that controlled for life stress, depressive symptoms, and medications. The mechanisms linking childhood trauma and cortisol levels in chronic pain are largely unexplored. Among the most plausible mediators are depression and PTSD, both of which are associated with childhood maltreatment and HPA dysregulation (36,37). Other data link individual differences in perceived stress and affect among healthy adults (38,39) and morning pain ratings in fibromyalgia patients (28) to basal cortisol levels. Thus, it is plausible that daily experiences of stress, physical symptoms, and affect in pain patients, if these stem from earlier traumatic experience, could help explain the association between childhood trauma history and cortisol. To date, this hypothesis remains untested. In summary, the limited evidence available suggests that abuse in childhood can lead to HPA axis abnormalities in fibromyalgia. However, whether the link between early trauma and HPA function is unique to individuals with fibromyalgia or can be accounted for or exacerbated by current psychopathology or daily symptoms remains to be determined. The purpose of the current investigation was to examine the relationships between reported childhood maltreatment and ambulatory basal cortisol secretion in women with chronic pain. We addressed four questions: 1) Are the links between childhood trauma and diurnal cortisol patterns, if they exist, similar for patients with fibromyalgia versus a chronic pain condition with a clear pathophysiology? 2) Does the association between childhood trauma and cortisol patterns depend on the type of maltreatment (sexual, physical, or emotional abuse; physical or emotional neglect)? 3) Does current psychopathology mediate or moderate the association between childhood trauma and adult cortisol patterns? 4) Do 472

daily experiences of pain, stress, mood, or sleep disturbance account for the relationship between childhood maltreatment and cortisol levels? To answer these questions, we drew on salivary cortisol and psychosocial measures collected over 30 days from a sample of 70 women who reported chronic pain associated with fibromyalgia and/or osteoarthritis. Osteoarthritis, a common pain condition associated with aging, is caused by the breakdown and eventual loss of cartilage in one or more joints. It affects 17% of adult women and 40% of women with fibromyalgia (40). Comparing subgroups of women with chronic pain, either associated with fibromyalgia or not, can help clarify whether HPA dysregulation post childhood maltreatment is unique to fibromyalgia. Because we assessed symptoms of both depression and PTSD, we could evaluate whether these common psychiatric sequelae of early trauma mediate or exacerbate observed HPA irregularities. Finally, with multiple assessments across 30 days, we were able to examine the extent to which proximate psychosocial factors are involved in the pathway from childhood maltreatment to deviant cortisol patterns. METHODS Participants The sample was drawn from an ongoing longitudinal study of changes in regional and widespread pain over time among women with the chronic pain conditions of combined fibromyalgia and osteoarthritis (FM group) or osteoarthritis only (OA group). Between May 2002 and March 2004, the current sample was recruited through physician referral, ads in the local newspaper, and fliers posted at fibromyalgia or chronic pain seminars. Potential participants were screened by telephone to determine eligibility. Eligibility requirements included: 1) female; 2) physician-confirmed diagnosis of either fibromylagia plus osteoarthritis or osteoarthritis only; 3) a current pain rating of ⬎20 on a 0 to 100 scale (0, “no pain” to 100, “pain as bad as it can be”); and 4) ability to engage in study activities. In addition, to ensure that participants in the two groups were comparable in the mutability of their symptoms, eligibility criteria for OA participants included onset of symptoms within the last 5 years or moderate self-reported worsening of symptoms in the past month, to a degree comparable to that of fibromyalgia participants (i.e., pain rating of ⬎40). Exclusion criteria included: 1) autoimmune or other comorbid disorders causing widespread pain, inflammation, and fatigue (e.g., polymyalgia rheumatica, ankylosing spondylitis); 2) pending litigation regarding the pain condition; and 3) use of daily corticosteroids. Osteoarthritis-only participants were also excluded if they had a comorbid disease with symptoms similar to fibromyalgia. The study was approved by the Institutional Review Board at Arizona State University. After completion of the initial eligibility screening and before their physicians were contacted for diagnosis confirmation, participants provided their written informed consent for all study activities. The current analysis includes data from the first 35 OA women and the first 35 FM group women aged ⱖ40 years who were enrolled in the larger study (final n ⫽ 257), yielding diagnostic groups roughly comparable in age. Based on physician confirmations of diagnosis supplemented by a tender point clinical examination, the 35 FM participants met the American College of Rheumatology criteria for fibromyalgia syndrome (41), all but three in combination with osteoarthritis;1 the 35 OA participants had osteoarthritis only.

1 The three women with fibromyalgia without osteoarthritis were screened into the study in error. Because analyses repeated after removing data from these women did not alter the main findings, we retained all 35 women with fibromyalgia in the reported analyses.

Psychosomatic Medicine 72:471– 480 (2010)

CHILDHOOD MALTREATMENT AND CORTISOL Procedure As part of the larger investigation of adaptation in chronic pain, participants completed the following four study components: a daily diary field assessment of symptoms, mood, and cortisol; an in-home assessment of physical and mental health symptoms; laboratory tests of stress reactivity under controlled conditions; and follow-up of illness course after 2 years. Only data from the field and home assessments are used in the current analysis. Before bedtime each evening on up to 30 consecutive days, participants completed diary reports on a laptop computer provided for this purpose. Only a single diary report could be completed each day, and diary reports were time-stamped to verify compliance. Diary questionnaires included measures of pain, fatigue, sleep quality, positive and negative affect, and stress. Over the same period, participants also collected saliva samples three times a day (at 10 AM, 4 PM, and 8 PM), using cotton salivettes (Sarstedt, Newton, North Carolina). To assess compliance, participants were given a 200-mL bottle containing enough swabs for 30 days, with a cap that registered all opening times (MEMS TrackCap, Aardex Ltd., Sion and Zug, Switzerland). Participants were told to open the bottle only at the scheduled collection times and to remove only one swab each time; they were provided with a digital alarm that beeped at the scheduled times as a reminder. Participants returned saturated swabs to salivette tubes, recorded the actual collection time on the tube, and at the end of each day, stored the new samples in their home freezer. In-home clinical assessments were conducted between 1 day and 27 days (mean, 7.0 days) after completion of the daily diaries and saliva collection. At this time, participants also completed questionnaires regarding experiences of childhood trauma and current depressive symptoms, and an interview for symptoms of PTSD. The frozen saliva samples were then taken to the laboratory and stored at ⫺20°C until analysis.

Measures Childhood Trauma Questionnaire The Childhood Trauma Questionnaire-short form (CTQ-sf), validated in clinical and community samples, is a self-report measure with 25 clinical and three validity items (42). Five subscales measure different types of maltreatment during childhood and adolescence: emotional abuse; physical abuse; sexual abuse; emotional neglect; and physical neglect. Each subscale consists of five items, scored on 5-point scales (1, “never true” to 5, “very often true”). In the current sample, Cronbach’s ␣ ranged from 0.73 for physical neglect to 0.96 for sexual abuse. Because different forms of maltreatment commonly co-occur, we examined the total CTQ-sf score as well as the five subscale scores in the present analyses.

Depressive Symptoms Depressive symptoms were assessed via self-report using the Hamilton Depression Inventory-Short Form (HDI-SF), which has 15 items that assess nine cognitive, somatic, and motivational symptoms of depression. Participants indicated on a 5-point scale (0, “not at all or rarely” to 4, “almost all of the time”) the extent to which, during the last 2 weeks, they experienced each symptom. The HDI-SF yields scores that correlate highly with those of other validated instruments assessing depressive symptomatology (43). In the current sample, Cronbach’s ␣ was 0.88.

PTSD PTSD symptoms were assessed by clinical interview, based on the SemiStructured Assessment for the Genetics of Alcoholism-II (44). This instrument is designed for use by lay interviewers and provides a diagnosis of PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Staff members were trained to conduct the interview by a licensed clinical psychologist and attended weekly group meetings to maintain consistency across interviewers throughout the course of the study. Individuals were coded as having a lifetime history of PTSD if they indicated that they had ever experienced one or more traumatic events that resulted in symptoms that included reexperiencing of the event, avoidance of circumstances related to the event, and hyperarousal. Psychosomatic Medicine 72:471– 480 (2010)

Daily Experience Participants rated their pain, affect, stress, and sleep in diaries completed at the end of each day, and a mean score was computed across the 30 days for each participant for each measure. Pain was assessed with the question, “What number describes your average level of pain today?,” with a response that could range from 0 indicating “no pain” to 100 indicating “pain as bad as it can be.” Positive affect and negative affect were assessed via ratings of 30 affect terms drawn from the Positive and Negative Affect Schedule-Expanded Form (45) on 5-point scales (1, “very slightly or not at all” to 5, “extremely”). The items, averaged across 30 days for each person, yielded a Cronbach’s ␣ coefficient of 0.98 for positive affect and 0.92 for negative affect. Interpersonal stress was obtained by averaging daily responses on the four items “Overall, how stressful were your relations with your {category filled in} today?” for friends, spouse/partner, family, and co-workers, each rated on a 4-point scale (1, “not at all” to 4, “extremely”). Sleep quality was assessed with the item “What number best describes your overall quality of sleep last night?,” with a response that could range from 0 indicating “extremely poor sleep” to 100 indicating “extremely good sleep.” Participants completed an average of 24 daily reports over the 30 days (80%), as confirmed by the electronic timestamps. Compliance was similar in the two groups (82% in FM; 78% in OA).

Salivary Cortisol: Laboratory Procedure and Sampling Compliance An in-house radioimmunoassay (Department of Reproductive Physiology, University of Lie`ge) was performed in duplicate on 50 ␮L of saliva, with salivary free cortisol in competition with a high-performance liquid chromatography preparation of cortisol-3CMO coupled with 2-125iodohistamine as tracer for specific antibodies raised against cortisol-3CMO-BSA (46). The lower detection limit of the assay was 0.2 nmol/L. The intra- and interassay coefficients of variation were ⬍5% and ⬍12%, respectively. All samples from an individual were analyzed in the same assay to reduce sources of variability. Three cortisol measures had values above the physiological range (⬎55 nmol/L) and were excluded from the statistical analysis. Of the remaining 5191 saliva samples, 3140 (61%) had both a self-reported collection time and an electronic time registration. These two time values were highly correlated (r ⫽.999, p ⬍ .001), differing by a median of 3.0 minutes. After exclusion of 131 samples with discrepancies of ⬎60 minutes, 5060 cortisol measures remained in the analysis. When monitored times were unavailable (n ⫽ 489), self-reported time data were used instead. Exclusion of these 489 samples from the analyses did not, however, alter the results. Mean collection times for morning, afternoon, and evening samples were 10:07 AM (n ⫽ 1666), 4:12 PM (n ⫽ 1692), and 8:09 PM (n ⫽ 1702). The mean difference between target time and collection time was only 7.3 minutes; however, 18 (0.4% of the total) saliva samples were taken at least 60 minutes before the target time, and 226 (4.9%) were taken at least 60 minutes after the target time. Rather than excluding these samples, we used actual collection times in the analysis. Over the 30 days, participants collected a median of 83 valid saliva samples each (range, 12–90). Only five of the 70 participants had ⬍30 cortisol measurements. Individual differences in compliance, defined as either the number of valid cortisol measures or average deviation of collection times from target times, were unrelated to CTQ-sf total or subscale scores, pain diagnosis (FM versus OA groups), PTSD, or depressive symptoms.

Statistical Analysis We used Stata, SE 10.1 for Macintosh (Stata Corporation, College Station, Texas), to estimate multilevel models, which take into account the hierarchical clustering of the data (47). In our case, the model used to estimate effects on cortisol had three levels: data were collected three times a day (measurement level); for 30 consecutive days (day level); clustered within participants (person level). However, variance components in a three-level model with no predictors (“empty model”) (48) indicated that day-level variance was negligible (0.004, compared with person-level variance of 0.123 and measurement-level variance of 0.440). Because the three-level model failed to converge but yielded almost 473

N. A. NICOLSON et al. identical results after 50 iterations as a two-level model, final models omitted the day level. We used maximum likelihood estimation to test fixed effects. Cortisol values were natural-log transformed to correct positive skew in their distribution. All independent variables were centered around the grand mean or dummy-coded, as appropriate. Estimated effects are thus expressed as unstandardized ␤ coefficients. The diurnal pattern of cortisol was fitted as a function of time (in hours), centered around the grand mean. Over the reported range of times, the distribution of log cortisol values was approximately linear, and the addition of polynomial terms did not improve model fit. The model allowed for cortisol intercepts and diurnal slopes to vary randomly across persons. In exploratory analyses, we tested the effects (both separately and together) of the following potential person-level confounders: age; education; income; body mass index; exogenous hormones; specific classes of medication (analgesics, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, antidepressants, anxiolytics, hypnotic sedatives, synthetic thyroid hormones, topical corticosteroids, inhaled steroids, antihypertensives, anticonvulsants); and total number of medications. Of these, only age and use of antihypertensives had p ⱕ.10 and were, therefore, retained in all subsequent multilevel analyses. To address our first hypothesis, we estimated effects of total childhood trauma score on cortisol level; addition of a CTQ by time interaction term to the model tested for effects of childhood maltreatment on cortisol diurnal slope. We investigated differences between FM and OA groups and whether the link between maltreatment and cortisol patterns was specific to fibromyalgia by adding a dummy variable diagnosis (FM was coded as “1”; OA was coded “0”) and its interaction with time of day to the model. In additional models, we examined the contributions of different forms of childhood maltreatment. Exploratory analyses were repeated for each of the five CTQ subscales separately. Because the different forms of maltreatment were intercorrelated, all five CTQ subscale scores and their interactions with time of day were entered as predictors in a final model to clarify whether certain forms of maltreatment were independently associated with cortisol level or diurnal slope. The hypothesized influences of PTSD and depression on HPA axis activity were also evaluated. To determine whether individual differences in measures of adult psychopathology might account for the effects of childhood maltreatment on cortisol patterns, we followed the analytic strategy recommended by Baron and Kenny (49) to establish mediation. When results of the multilevel analyses indicated a significant link between childhood maltreatment and cortisol levels, we regressed lifetime PTSD diagnosis and current depressive symptoms on the independent CTQ variable. If CTQ scores were correlated with either or both of these putative mediators, additional multilevel models were estimated, with PTSD diagnosis (dummy-coded), depressive symptoms (grand mean centered), and their interaction included, along with the CTQ variable, as predictors. Even without playing a causal role in the pathway from childhood maltreatment to HPA abnormalities, psychopathology could theoretically moderate (amplify or reduce) the effects of early maltreatment on cortisol secretion. Separate multilevel models were, therefore, estimated to assess interactions with CTQ total score, and threeway interactions with CTQ score and time of day, for lifetime PTSD and current depressive symptoms. Finally, we investigated whether childhood maltreatment effects on cortisol might be proximally mediated by daily symptoms by 1) examining correlations between CTQ scores and levels of pain, affect, stress, and sleep disruption averaged over the month-long sampling period; and 2) testing mediation of the childhood maltreatment-cortisol relationship by including these aggregated daily experience variables in separate multilevel regression models. Unless otherwise noted, statistical tests were two-tailed, with ␣ ⫽ 0.05. In the regression models, ␤/standard error (SE) is approximately Z distributed.

RESULTS Participant Characteristics The majority of the sample was Caucasian (90%), currently married or living with a partner (69%), and employed at least part time (59%). Participants had a median of 1 to 3 years of college education, and median household income 474

was $40,000 –$49,999. FM and OA groups did not differ in any of these demographic characteristics. Comparative results for variables used in the current statistical analyses are summarized in Table 1. FM participants were on average 5 years younger than the OA participants. In addition, FM participants reported more severe depressive symptoms and average daily pain, compared with OA subjects, whereas daily positive affect was lower. FM and OA groups were similar in menopausal status, body mass index, and use of exogenous hormones (mainly hormone replacement therapy), and, as expected in chronic pain patients in this age range, many participants in both groups reported using prescription and over-the-counter medications. The total number of different medications (including exogenous hormones) used by an individual ranged from 0 to 7, with a median of 2. As shown in Table 1, FM participants were significantly more likely to use analgesics, antidepressants, and anxiolytics. Reported Childhood Maltreatment Participants reported a wide range of childhood maltreatment experiences (Table 2). Women in the FM group, compared with those in the OA group, tended to have higher mean total scores on the CTQ-sf and, in particular, the abuse subscales; however, no difference between the two groups was statistically significant. Scores on the five subscales of the CTQ-sf were intercorrelated, indicating that participants had often experienced more than one form of abuse or neglect in childhood. Diurnal Cortisol Patterns in Relation to Maltreatment and Pain Diagnosis Table 3 shows means and ranges for the cortisol values at each of the three diurnal sampling times, as well as correlations between mean cortisol level and total childhood maltreatment score. These descriptive findings indicate the expected decline in cortisol secretion over the day and a possible association between cortisol levels and maltreatment in both FM and OA subgroups. Multilevel regression results confirm these patterns. In the final model, summarized in Table 4, overall severity of childhood maltreatment (total CTQ-sf score) was associated with higher cortisol levels (significant CTQ main effect, standardized ␤ ⫽ 0.17) throughout the day (nonsignificant CTQ by time effect). Calculated according to Snijders and Bosker (48), childhood maltreatment score explained 12.2% of the between-individual variance in log cortisol levels that remained after controlling for time of day, age, and antihypertensive use. Pain diagnosis (FM versus OA group), in contrast, was not a significant predictor of either cortisol levels or diurnal slopes. Extension of the model with interaction terms provided no evidence that the relationship between childhood maltreatment and cortisol secretion was specific to fibromyalgia (CTQ by Diagnosis: ␤ ⫽ 0.002, SE ⫽ 0.004, p ⫽ .62; CTQ by Diagnosis by Time: ␤ ⫽ 0.000, SE ⫽ 0.001, p ⫽ .97). To illustrate these findings, Figure 1 shows observed cortisol profiles for women with high versus low (median split) total Psychosomatic Medicine 72:471– 480 (2010)

CHILDHOOD MALTREATMENT AND CORTISOL TABLE 1.

Participant Characteristics in FM and OA Groups FM (n ⫽ 35)

OA (n ⫽ 35)

pa

Mean

(SD)

Mean

(SD)

Age BMI Depressive symptoms Daily diary reports Pain (0–100) Positive affect (1–5) Negative affect (1–5) Stress (1–5) Sleep quality (0–100)

53.5 31.0 9.8

8.2 8.4 5.0

58.4 31.6 7.2

8.7 8.5 5.2

.02 .78 .02

61.6 2.1 1.5 1.5 57.1

12.5 0.6 0.4 0.4 14.1

46.3 2.7 1.4 1.4 61.4

17.0 1.1 0.5 0.3 17.1

⬍.001 .02 .07 .12 .26

Somatic Characteristics

n

(%)

n

(%)

p

Postmenopausal Medications HRT OC Antihypertensives Analgesics NSAIDS Antidepressants Anxiolytics

27

77%

32

91%

.10

15 2 11 20 8 22 8

43% 6% 31% 57% 23% 63% 23%

16 0 9 9 12 7 2

46% 0% 26% 26% 34% 20% 6%

.81 .49 .60 .01 .29 ⬍.001 .04

To test for group differences, t tests were used for continuous variables and ␹2 tests for categorical variables. FM ⫽ fibromyalgia group; OA ⫽ osteoarthritis group; SD ⫽ standard deviation; BMI ⫽ body mass index; HRT ⫽ hormone replacement therapy; OC ⫽ oral contraceptives; NSAIDS ⫽ nonsteroidal anti-inflammatory drugs. a

TABLE 2.

CTQ Subscale

EmAb PhysAb SexAbb EmNeg PhysNeg Total score

Range

% Above Clinical Cutoffa

5–25 5–24 5–25 5–22 5–19 25–106

44% 33% 25% 20% 33%

Childhood Maltreatment (CTQ-Short Form) Scores

FM Mean (SD)

OA Mean (SD)

p (M-W)

11.4 (5.8) 8.3 (3.9) 8.9 (5.9) 10.7 (5.6) 7.1 (3.2) 46.4 (19.9)

9.0 (5.0) 7.1 (3.9) 6.7 (4.3) 9.5 (4.5) 7.1 (3.0) 37.9 (15.2)

0.07 0.06 0.06 0.47 0.75 0.06

Spearman Correlations (rs) PhysAb

SexAb

EmNeg

PhysNeg

0.67* — — — —

0.45* 0.46* — — —

0.73* 0.51* 0.43* — —

0.50* 0.46* 0.20 0.56* —

a Based on thresholds established by Walker et al. (50) to identify clinically significant levels of maltreatment, individuals with subscales scores of ⱖ8 met the criteria for physical abuse, physical neglect, and sexual abuse; the criteria for emotional abuse and emotional neglect were scores of ⱖ10 and ⱖ15, respectively. b One participant did not complete the sexual abuse subscale items. * p ⬍ .001. FM ⫽ fibromyalgia group; OA ⫽ osteoarthritis only group; CTQ ⫽ Childhood Trauma Questionnaire; M-W ⫽ Mann-Whitney test; PhysAb ⫽ physical neglect; SexAb ⫽ sexual abuse; EmNeg ⫽ emotional neglect; PhysNeg ⫽ physical neglect; EmAb ⫽ emotional abuse.

TABLE 3.

Cortisol Levels (nmol/L) and Correlations With Total Childhood Maltreatment Score rs Correlation With CTQ Score

Sampling Time

10 AM 4 PM 8 PM

Mean (SD) (n ⫽ 70)

4.7 (2.4) 2.5 (1.1) 1.8 (1.0)

Range

1.5–12.8 1.0–7.1 0.6–6.1

Total Sample (n ⫽ 69)

FM (n ⫽ 35)

OA (n ⫽ 34)

rs

pⱕ

rs

pⱕ

rs

pⱕ

.24 .27 .12

.05 .03 .34

.24 .35 .12

.17 .04 .51

.28 .23 .17

.11 .20 .34

CTQ ⫽ Childhood Trauma Questionnaire; SD ⫽ standard deviation; FM ⫽ fibromyalgia group; OA ⫽ osteoarthritis group. Psychosomatic Medicine 72:471– 480 (2010)

475

N. A. NICOLSON et al. TABLE 4.

Multilevel Model: Estimated Effects of Childhood Maltreatment and Pain Diagnosis on Cortisol Level and Diurnal Slope Fixed Effects

Intercept CTQ (total score) CTQ ⫻ Time FM FM ⫻ Time Time of day Age Antihypertensives

Coefficient (␤)

SE

Z

0.729 0.007 ⫺0.000 ⫺0.010 ⫺0.013 ⫺0.093 0.016 0.181

0.057 0.002 0.000 0.080 0.009 0.006 0.005 0.086

12.76 3.23 ⫺0.67 ⫺0.18 ⫺1.48 ⫺15.12 3.17 2.10

95% CI 0.617 0.003 ⫺0.001 ⫺0.171 ⫺0.030 ⫺0.105 0.006 0.012

0.841 0.011 0.000 0.143 0.004 0.081 0.025 0.349

p

Interpretation# (Raw Cortisol Levels)

⬍.001 .001 .51 .86 .14 ⬍.001 .002 .035

2.07 nmol/L (at mean time) 0.7% increase per unit CTQ NS NS NS 10% decrease per hour 1.6% increase per year 19.8% increase if used

Random Effects Parameters

Variance components Var (person-specific means) Var (diurnal slope) Var (residual)

Estimate

SE

0.0890 0.0010 0.2485

0.0158 0.0002 0.0051

95% CI

0.063 0.001 0.239

0.126 0.002 0.259

SE ⫽ standard error; CI ⫽ confidence interval; CTQ ⫽ Childhood Trauma Questionnaire; FM ⫽ fibromyalgia group; Var ⫽ variance. The model is based on 4972 observations nested within 69 participants. Time of day (hr), age, and CTQ score are centered on the sample means; pain diagnosis is coded as FM group ⫽ 1 and OA group ⫽ 0. Effects of the following variables were evaluated in preliminary analyses: education, family income, body mass index, and classes of medication listed under Statistical Analysis). Except for age and antihypertensive use, none of the estimates for the control variables approached statistical significance (all p ⬎ .10), and these variables were, therefore, excluded from the final models. Regression coefficients are unstandardized. Intraclass Correlation Coefficient (between-person) ⫽ 0.2637. #% change in raw cortisol per unit change in predictor ⫽ 关exp(␤)兴 ⫺ 1.

Figure 1. Diurnal salivary cortisol profiles as a function of childhood maltreatment. High and low levels of maltreatment were defined by a median split (ⱖ35 ⫽ high) for Childhood Trauma Questionnaire (CTQ)-short form total scores over the entire sample. Mean cortisol values are shown for fibromalgia (FM) and osteoarthritis (OA) subgroups reporting high versus low maltreatment. Error bars indicate standard errors. The numbers in each subgroup represent FM/CTQ high ⫽ 21; FM/CTQ low ⫽ 14; OA/CTQ high ⫽ 14; OA/CTQ low ⫽ 20.

scores for childhood maltreatment. Although FM participants tended to report more severe childhood maltreatment than OA participants, pain diagnosis did not seem to modulate the positive association between maltreatment and adult cortisol levels. CTQ Subscale Analyses Separate multilevel models tested the effects of each of the five forms of maltreatment measured by the CTQ; here, significance ␣ was set at 0.01 to take into account repeated testing. Results indicated significant positive associations be476

tween cortisol levels and emotional abuse (␤ ⫽ 0.0245, SE ⫽ 0.0071, standardized ␤ ⫽ 0.18, p ⫽ .001) and sexual abuse (␤ ⫽ 0.0230, SE ⫽ 0.0072, standardized ␤ ⫽ 0.16, p ⫽ .002). Effects of emotional neglect (␤ ⫽ 0.0175, SE ⫽ 0.0075, standardized ␤ ⫽ 0.12, p ⫽ .019), physical abuse (␤ ⫽ 0.0197, SE ⫽ 0.0104, standardized ␤ ⫽ 0.11, p ⫽ .058), and physical neglect (␤ ⫽ 0.0230, SE ⫽ 0.0138, standardized ␤ ⫽ 0.10, p ⫽ .095) were positive but nonsignificant. In the above models, interactions with time of day were also nonsignificant, indicating no association between specific forms of maltreatment and cortisol diurnal slope. Psychosomatic Medicine 72:471– 480 (2010)

CHILDHOOD MALTREATMENT AND CORTISOL Because different forms of maltreatment tended to cooccur, the analysis was repeated with all subscale scores entered simultaneously. More severe sexual abuse (␤ ⫽ 0.018, SE ⫽ 0.009, Z ⫽ 2.11, standardized ␤ ⫽ 0.13, p ⫽ .035) and emotional abuse (␤ ⫽ 0.035, SE ⫽ 0.014, Z ⫽ 2.45, standardized ␤ ⫽ 0.26, p ⫽ .014) remained associated with higher overall cortisol levels; these effects can be interpreted as a 1.8% increase in raw cortisol level for each unit increase in sexual abuse score and a 3.6% increase in cortisol for each unit increase in emotional abuse. This model explained 19.9% of the variance in cortisol levels, after controlling for time and potential confounders. Interaction effects for the CTQ subscales with time of day revealed a flatter diurnal decline, in combination with higher overall cortisol levels, in women who reported severe sexual abuse (␤ ⫽ 0.002, SE ⫽ 0.001, Z ⫽ 2.29, p ⫽ .022). However, the inclusion of interactions between CTQ subscales and time of day did not significantly improve the model, compared with the model with main effects only (likelihood ratio test, ␹2 ⫽ 8.31, p ⫽ .14). Role of Psychopathological Symptoms On average, women in this sample showed a relatively low level of depressive symptoms (mean, 8.5; standard deviation, 5.2; range, 0 –23), with eight participants reporting symptoms in the clinical range (HDI-sf ⱖ17). Clinical assessment of PTSD symptoms identified 13 women meeting lifetime diagnostic criteria for PTSD; of these, eight had experienced PTSD symptoms in the last year. Women reporting more severe childhood maltreatment had more current depressive symptoms (Spearman rs ⫽ 0.40, p ⬍ .001) and were more likely to have a lifetime diagnosis of PTSD (␤ ⫽ 0.048, SE ⫽ 0.018, p ⱕ .01, Exp(␤) ⫽ 1.049, 95% confidence interval, 1.014 –1.086). This suggested that adult cortisol abnormalities in earlier maltreated women might have been due to current psychiatric disorder. However, addition of either or both of these variables as predictors in the multilevel regression of cortisol on CTQ total score did not significantly reduce the association between reported maltreatment and cortisol levels. Moreover, current depressive symptoms (␤ ⫽ 0.001, SE ⫽ 0.008, Z ⫽ 0.18, p ⫽ .86) and lifetime PTSD diagnosis (␤ ⫽ 0.025, SE ⫽ 0.106, Z ⫽ 0.24, p ⫽ .81) showed no significant associations with cortisol level. These findings rule out a causal role for these forms of psychopathology in explaining the link between early traumatic experiences and adult cortisol secretion. Nevertheless, psychopathology might amplify the effects of maltreatment on cortisol. To evaluate this possibility, separate multilevel analyses tested interaction terms: PTSD diagnosis by CTQ (total score, sexual abuse, emotional abuse) and depressive symptom score by CTQ (total score, sexual abuse, emotional abuse). None of the estimated effects was significant. Influence of Current Daily Symptoms on Cortisol Correlations between total CTQ scores and daily experience variables, recorded at the end of each day and averaged over the month-long sampling period, revealed significant Psychosomatic Medicine 72:471– 480 (2010)

TABLE 5. Multilevel Regression Estimates of the Effects of Average Daily Experience Variables on Cortisol Levels, in Relation to Childhood Maltreatment Effects Coefficient (␤)

Z

p

Intercept CTQ (total score)

0.723 0.007

3.25 ⬍.001

(a) NA (b) CTQ, controlling for NA

0.116 0.007

1.22 3.15

(a) PA (b) CTQ, controlling for PA

0.028 0.008

0.61 .540 3.55 ⬍.001

(a) Pain (b) CTQ, controlling for Pain

0.001 0.007

0.47 .638 3.20 ⬍.001

(a) Stress (b) CTQ, controlling for Stress

0.018 0.007

0.15 .882 3.18 ⬍.001

⫺0.003 0.007

⫺1.24 .214 3.41 ⬍.001

(a) Sleep Quality (b) CTQ, controlling for Sleep Quality

.224 .002

CTQ ⫽ Childhood Trauma Questionnaire; NA ⫽ negative affect; PA ⫽ positive affect. All models are based on 4972 observations nested within 69 participants. The dependent variable is log cortisol. Models control for time of day, age, and antihypertensive use. All continuous variables are centered around the sample grand means. For each daily experience variable, an estimate (a) was first obtained for its independent effect on cortisol levels. In a second step (b), estimates were obtained for the effect of CTQ on cortisol, after controlling for the daily experience variable. Regression coefficients are unstandardized.

associations between childhood maltreatment and daily affect (negative affect: rs ⫽ 0.31, positive affect: rs ⫽ ⫺0.29, both p ⱕ .05) and nonsignificant trends for pain and interpersonal stress (for both, rs ⫽ 0.22, p ⫽ .07). Sleep quality, on the other hand, showed no relationship to CTQ scores (rs ⫽ 0.06, p ⫽ .61). A series of multilevel regression analyses with log cortisol as outcome measure and each of the averaged daily experience variables as predictor further evaluated whether average levels of affect, pain, stress, or sleep quality might mediate the observed association between CTQ total scores and cortisol levels. As summarized in Table 5, results indicated no significant effects of the daily experience variables on cortisol levels and no reduction in the strength of the CTQ-cortisol relationship after addition of these predictors to the models. DISCUSSION In this sample of women with chronic pain, self-reported childhood maltreatment was associated with higher salivary cortisol throughout the day, over 30 days of sampling. When different forms of abuse and neglect were examined separately, sexual abuse and emotional abuse emerged as the strongest predictors of cortisol levels. In addition, when other forms of maltreatment were controlled for, women reporting the most severe sexual abuse displayed not only higher cortisol levels but also flatter diurnal slopes. Although in line with meta-analytic findings concerning sexual abuse (19), this effect on diurnal slope was weak and requires replication in a larger sample. The observed association between emotional 477

N. A. NICOLSON et al. abuse and higher cortisol was surprising, as this form of maltreatment seems more subjective and less threatening than, for example, physical abuse. Recent studies have confirmed, however, that emotional abuse (usually parental verbal aggression) is a highly toxic form of childhood maltreatment (51– 53), showing moderate-to-large associations with adult psychiatric symptoms (54). In contrast to abuse, neglect showed no relationship with HPA activity, although reports of abuse and neglect were moderately correlated in our sample. In summary, the current findings add to the evidence that maltreatment in childhood can induce long-term alterations in HPA function and support the notion that abuse is more potent than neglect in this regard (16). Our finding of elevated basal cortisol in previously abused women is striking in light of the moderate levels of reported maltreatment in our sample. Although four of the five CTQ subscale scores seem to be slightly higher on average in both FM and OA groups than those in a normative sample of women, all five subscale scores were lower than those in fibromyalgia patients recruited from pain clinics (55). CTQ scores closely resemble those in the research of Weissbecker et al. (7), who studied fibromyalgia patients recruited from the community, as in our sample. Compared with the current results, reports of low morning cortisol levels and flatter diurnal slopes in association with sexual and physical abuse in that study are thus unlikely to reflect different degrees of maltreatment but rather differences in methodology; for example, the timing of the morning samples in relation to awakening and possible effects of poor compliance with the sampling protocol. As in the current study, childhood emotional abuse was associated with higher cortisol in the late afternoon and evening (7). Some researchers have postulated that childhood trauma plays an etiologic role in the development of fibromyalgia and that HPA axis dysregulation mediates that relationship (5,7,56). Correspondingly, we had expected to find a stronger relationship between childhood trauma and cortisol in women with fibromyalgia compared to those with osteoarthritis only. However, not only did we fail to find a group difference in overall cortisol levels or diurnal secretory, but the absence of significant diagnosis by CTQ interaction effects indicates that childhood maltreatment was similarly associated with cortisol patterns in both groups. It is important to note that the fibromyalgia participants had only marginally higher total CTQ scores than the osteoarthritis participants; it remains possible that more extreme levels of maltreatment would reveal a more specific relationship with cortisol patterns in fibromyalgia. If so, previous reports of elevated diurnal cortisol (27) or other HPA abnormalities in fibromyalgia may, in part, reflect the unmeasured effects of childhood adversity. It is likely that the heterogeneous nature of fibromyalgia contributes to the inconsistent results across studies. Fibromyalgia is often comorbid with health problems that are themselves associated with HPA axis dysregulation, including other chronic pain conditions, depression, anxiety, and chronic fatigue syndrome (25,34,57,58). Childhood trauma also in478

creases the risk of developing depression and PTSD (51,53), with accompanying HPA abnormalities (52). We, therefore, explored whether depressive symptoms or PTSD (past or current) might account for the robust association between reported childhood maltreatment and adult cortisol levels. This was not the case: the associations held regardless of affective symptomatology. However, low symptom levels in the current sample, with only 11% experiencing clinical levels of depressive symptoms and another 11% meeting the criteria for recent PTSD, may have constrained our ability to detect moderating effects. Moreover, the index trauma associated with PTSD was not necessarily childhood abuse. Evidence from samples without chronic pain suggests that the effects of early trauma on HPA activity are most apparent among women who develop abuse-related PTSD symptoms (18,59). Whether this pattern holds in patients with chronic pain remains to be determined. In general, progress in elaborating the nature and extent of HPA abnormalities in chronic pain conditions may require more fine-grained evaluation of subgroups differentiated by characteristics such as comorbidities and history of maltreatment. We also examined whether more proximate daily life variables contributed to the relationship between childhood maltreatment and cortisol. Maltreated women reported higher negative affect and lower positive affect, averaged over all diary reports, but neither daily affect, pain, interpersonal stress, or sleep disturbance was associated with cortisol levels. Other studies (27,28) of patients with chronic pain have similarly found little correspondence between daily experience variables and cortisol, in contrast to studies (39,40) of healthy adults, where positive affectivity has been associated with lower cortisol and negative affectivity with higher cortisol. Among the possible explanations for these discrepant findings is that a pain condition is itself a chronic stressor, altering the links between affectivity and HPA activity. In addition, despite the large number of cortisol measures and the reliable estimates of individual daily experience from daily reports collected over a month, the relatively small number of participants meant that statistical power to investigate individual differences was limited. This study has some other limitations. First, retrospective measures of maltreatment may be subject to reporting bias; for example, women with high negative affectivity or depressive symptoms might be more likely to report past maltreatment, explaining the correlations between CTQ scores and current symptoms. However, the finding that the effect of reported maltreatment on cortisol remained significant after controlling for depression and negative affect means that any such reporting bias would not invalidate our conclusions. Second, because our sample was composed of middle-aged to elderly women with chronic pain, the findings may not generalize to other individuals, including men and adults without a chronic pain condition. Moreover, inclusion criteria established for the larger study meant that almost all of the FM participants also had osteoarthritis. Osteoarthritis is a very common comorbid condition in fibromyalgia, and there is no a priori reason to Psychosomatic Medicine 72:471– 480 (2010)

CHILDHOOD MALTREATMENT AND CORTISOL postulate that fibromyalgia in patients with comorbid osteoarthritis has a different etiology than fibromyalgia in patients without osteoarthritis. Nor is it clear that previous studies of fibromyalgia assessed and excluded participants with comorbid osteoarthritis. Nevertheless, it remains possible that a fibromyalgia-only sample would have yielded different results. Third, the majority of our participants were taking medications to manage their medical conditions; however, we found no evidence that these medications influenced cortisol levels (with the possible exception of antihypertensives, which we controlled for in all analyses). Fourth, we obtained reliable estimates of diurnal cortisol levels and slopes, but we chose not to assess the cortisol awakening response in order to limit expense and participant burden in this 30-day study. The cortisol awakening response may have provided unique information regarding the consequences of childhood maltreatment for adult HPA activity (7,60). Finally, without measures of cortisol reactivity to stressors or function at other levels of the axis, the current study presents only a partial picture of HPA activity. Several important strengths of the study are also noteworthy. First, our analyses were based on a large group of pain patients, the majority of whom provided ⬎80 cortisol samples to assess diurnal profiles across 30 days. The duration of the study allows for separate analyses of within-person associations between daily experience and cortisol; however, it should be noted that 30 days is longer than necessary to detect between-group differences in cortisol levels or diurnal slopes (61,62). The findings reported here were also statistically significant when only the first 7 days of data were included in the models. Because of reports of inadequate compliance with instructions in real-life studies with fixed sampling schedules (63), compliance with the timing of both cortisol samples and daily diary reports was verified electronically. We achieved a high rate of compliance and were able to include actual collection time in models predicting cortisol values (64). Each of these aspects of the methodology increases our confidence in the reliability and validity of the data. In summary, results underscore the importance of evaluating childhood maltreatment in fibromyalgia and other chronic pain conditions, in particular, to clarify the origin and etiological significance of HPA axis dysregulation. Additional research is needed to identify factors that mediate or moderate the link between childhood maltreatment and HPA axis function, including comorbid syndromes, developmental timing and type of maltreatment, subsequent experiences of violence or abuse, and ongoing positive and negative interpersonal relations. Research along these lines has the potential to inform the development of better interventions to reduce the deleterious effects of childhood maltreatment.

3.

4. 5. 6. 7. 8. 9.

10.

11.

12. 13. 14. 15. 16. 17.

18. 19. 20.

21. 22.

23.

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