Altered cortisol response in sober alcoholics: An examination of contributing factors

Alcohol, Vol. 13. No. 5, pp. 4 9 3 4 9 8 , 1996 Copyright ~ 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0741-8329/96 $15.00 + .00

PII S0741-8329(96)00043-2

ELSEVIER

Altered Cortisol Response in Sober Alcoholics: An Examination of Contributing Factors NANCY

C. B E R N A R D Y , * A N D R E A C. K I N G , .1 O S C A R A. P A R S O N S t A N D W I L L I A M R. L O V A L L O *

*Behavioral Sciences Laboratories, Veterans Affairs Medical Center and ?Department o.f Psychiatry and Behavioral Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 R e c e i v e d 7 J u n e 1995; A c c e p t e d 8 M a r c h 1996 BERNARDY, N. C., A. C. KING, O. A. PARSONS AND W. R. LOVALLO. Altered cortisol response in sober alcoholics:An examination of contributingfactors. ALCOHOL 13(5) 493-498, 1996.--We have previously reported an attenuated plasma cortisol stress response in alcoholics abstinent from alcohol up to 4 weeks. The present study replicates and extends these findings by examining urinary cortisol levels in detoxified alcoholics (n = 40) and controls (n = 14) at rest and following mental arithmetic and isometric handgrip stress. Although the groups had similar baseline cortisol levels, the alcoholics showed an attenuated cortisol response to the combined stressors. This cortisol response reduction was unrelated to potential confounds such as smoking, liver function, age, depression, or anxiety. A multivariate model showed a trend for an association between severity of withdrawal and alcoholics' poststress cortisol levels. Although these results indicate decreased adrenocortical response to biobehavioral stress in alcoholics abstinent up to four weeks, higher stress cortisol values were seen in the patients with the most severe withdrawal symptoms. Alcoholism

Cortisol

Endocrine system

Withdrawal

T H E hypothalamic-pituitary-adrenocortical axis (HPAC) is adversely affected by chronic alcohol abuse (34). Both acute alcohol exposure and current withdrawal have been associated with increased levels of adrenocorticotropic hormone and cortisol (1). Although elevated cortisol levels have been observed in actively drinking alcoholics (35), chronic alcohol exposure may or may not sustain activation of the HPAC axis. Hormonal tolerance to chronic ethanol often develops, ranging from a mild loss of alcohol-induced activation of the HPAC axis to an actual downregulation of receptors (34). Human and animal work has indicated that the ability of the HPAC axis to respond to stress is also impaired by chronic alcohol exposure (5,8,34). Although the mechanisms underlying these endocrine disturbances are not completely understood, recent studies have proposed that the central nervous system and the corticotropin-releasing factor (CRF) neuron are the primary sites of alcohol's effects on the H P A C axis (33,34). Other work has suggested that increased severity of withdrawal symptoms in alcoholics may coincide with HPAC axis

alterations (1,2). Alcoholic patients who have experienced multiple withdrawals may show changes in the stress response system that possibly contribute to physiological disturbances for weeks to months after cessation of drinking (2,13). However, one of the problems in trying to determine the effects of chronic alcohol exposure on the HPAC axis has been the need for separating the effects of alcohol from coexisting liver disease, malnutrition, and depression (34). Other stressors, such as the underlying fluctuations in cortisol secretion due to intoxication and sympathetic hyperactivity associated with ethanol withdrawal, are known to contribute to axis disturbances (2,6). In addition, nicotine use in alcoholics may present another confound. Nicotine has been shown to increase plasma cortisol in persons who smoke between one and two packs of cigarettes per day (32). This level of smoking is characteristic of chronic alcoholics. To our knowledge, only two studies have examined the HPAC response of alcoholics to a nonpharmacological challenge. Margraf et al. demonstrated alcoholics' attenuated cor-

Requests for reprints should be addressed to Nancy C. Bernardy, Ph.D., Substance Abuse Treatment Unit, Yale University Department of Medicine, 1 Long Wharf, P.O. Box 18, New Haven, CT 06511. ~Current address: Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10011. 493

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tisol response to a psychological stressor, preoperative stress (21). This study compared only four alcoholics with four controls and did not control for potential differences in perceived distress or affective status between the groups. The other study, conducted in our laboratories by Errico and colleagues, demonstrated an attenuated cortisol response to a combination of mental arithmetic and a cold pressor task in 52 abstinent alcoholics compared to 30 matched nonalcoholic controls (11). A limitation of both of these studies is that potential confounding factors which could have influenced cortisol production were not addressed. The purpose of the present study was to investigate cortisol response to two moderately aversive stressors, mental arithmetic and isometric handgrip exercise, in abstinent alcoholics and nonalcoholic controls using urinary samples. The specific aims were to determine if: a) the alcoholics manifested an attenuated cortisol response to the two laboratory stressors; b) the alcoholics perceived the stressors differently than controls; c) cortisol activity was related to severity of withdrawal symptoms; and d) psychological factors (such as depression and anxiety) or other potential confounders (such as nicotine use, impaired liver function, or other drinking parameters) were related to cortisol response.

questionnaires for alcohol consumption, a 20-min rest period, a 5-min isometric handgrip task, a 20-min rest period, a 10min mental arithmetic task, and a 20-min recovery period. For each group, subjects were counterbalanced for task order. A 20-min interview assessed withdrawal symptoms and family history of alcoholism, and a poststress urine sample was collected at 1115-1130 h.

Laboratory Stressors Handgrip task. Isometric handgrip was performed using a Lafayette Instrument 78010 Hand Dynamometer (Lafayette Instruments, Lafayette, IN) calibrated from 0 to 100 kg. Grip strength was defined as the average of three maximum grip measurements. Handgrip was maintained for 5 min at 20% of grip strength. This task has been shown to be effective in activating both vascular and cardiac responses (9). Mental arithmetic. Subjects were required to perform mental calculations for 10 min. Each participant was given a fourdigit number and then required to subtract 7 from the answer in serial fashion for 50 responses. A similar procedure has been found to increase urinary cortisol excretion in male college students (20). Mood States Questionnaire

METHOD

Subjects" Participants were 40 sober male alcoholics and 14 matched male community controls. All subjects were between the ages of 21 to 51 years, inclusive, and had at least a 9th grade education. Alcoholics were inpatients in 28-day units at the Oklahoma City Veterans Affairs Medical Center and the Norman, Oklahoma Alcohol and Drug Treatment Center, who met DSM III-R criteria for alcohol dependence (3). Only those alcoholics who had their last alcohol intake within 3 days of hospital admission were considered for the study. In this sample, 71% of the patients were prescribed standard benzodiazepine treatment (ativan or librium) the first few days of withdrawal. However, all patients were medication free at the time of testing. Serum liver enzyme profiles were measured at admission in each patient. Controls were normotensive social drinkers ( < 4 drinks/ day) or abstainers recruited through local newspaper advertisements. Patients and controls were excluded for obesity ( > 30% ideal body weight), significant other drug abuse, history of neurological disorders, major affective disorder or a diagnosis of posttraumatic stress disorder, hypertension, liver disease, endocrine disease, or the use of medication that could alter endocrine functioning. All subjects signed a consent form approved by the Institutional Review Board of the University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center and were paid for participation.

Procedure All patients were tested at 3-4 weeks postadmission. Subjects refrained from caffeine and nicotine consumption and consumed a low-fat breakfast the morning of testing. Controls refrained from alcohol consumption for at least 24 h prior to testing. Breathalyzer tests conducted at testing via a portable model Lion Alcolmeter SD-2 (MPD, Inc., Owensboro, KY) were negative for expired alcohol in all subjects. Testing began at 0800 h and consisted of: collection of a baseline urine sample (between 0800 and 0830 h), completion of several

Subjects reported their affective responses to the laboratory challenges before and after each task using a 13-item questionnaire adapted from Frankenhauser (12). Items included degree of perceived control, stimulation, distress, effort, concentration, tenseness, interest, irritability, tiredness, boredom, impatience, pleasantness, and difficulty. Items were combined to form two scales [adapted from Lundberg (19)]: an activation subscale using ratings for effort, tension, concentration, interest, and stimulation along with a distress subscale consisting of impatience, irritation, distress, and reversed ratings for pleasantness and control.

Psychological Characteristics Given the association of psychological status and altered H P A C activity (16), subjects were administered two reliable and valid instruments of affective states, the Beck Depression Inventory (BDI) and the Spietberger State Anxiety Inventory (STAI) (4,30). Alcoholics have usually scored significantly higher on both measures than controls in our research although their means have not been in the clinically significant range (10).

Cortisol Assays Following consent and the breathalyzer test, each subject was given a 100-ml container and asked to void. The sample reflected the approximate 0630-0830 h time interval. A second urine sample was collected at the end of the testing session reflecting activity from 0830-1130 h. For each sample, 7 ml was immediately pipetted at original pH. Samples were then frozen at -70°C until assayed. Cortisol analyses were performed with a TDxFLx assay utilizing fluorescence polarization immunoassay method FPIA; Abbott Laboratories, North Chicago, IL). The F P I A uses a fluorescent tracer to detect the relative binding of the specimen analyte and analytetracer. In determining cortisol specificity, the highest cross-reactivity found in this assay was 9.9% for ll-deoxycortisol. Sensitivity was determined to be 0.64 Ixg/dl with 95% confidence. The intra- and interassay coefficients of variation were tess than 8% and 6%, respectively. Cortisol concentrations

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495

TABLE 1 DEMOGRAPHIC, PSYCHOLOGICAL, AND PHYSIOLOGICAL VARIABLES Variable Age (years) Education (years) Shipley (verbal age) BDI STAI

Controls

Alcoholics

34.1 (1.3) 12.9 (0.3) 16.8 (0.5) 3.3 (0.6) 43.6 (2.3)

36.2 (1.1) 12.2 (0.5) 16.0 (0.3) 7.9 (1.1)* 51.4 (1.4)t

Mood States Scales Activation Prestress Poststress Distress Prestress Poststress

3.6 (0.5) 5.2 (0.4)

4.1 (0.4) 5.6 (0.5)

3.4 (0.6) 5.6 (0.4)

3.8 (0.4) 5.5 (0.5)

Nicotine use (No. cigarettes/day) SGOT (IU/L) Drinking variables chronicity (years) QFI WAQ total score

7.2 (3.3) --0.4 (0.1) --

26.6 (2.5)¢ 59.0 (7.4) 14.9 (0.9) 13.0 (1.6)* 28.2 (11.5)

Values shown are mean with SEM in parentheses. Controls, n = 14; alcoholics, n 40: BDI = Beck Depression Inventory, STAI = Spielberger State Anxiety Inventory. Nicotine use measured as number of cigarettes smoked per day, SGOT - serum glutamic-oxaloacetic transaminase. Drinking frequency and quantity measures were based on subject report for the 6 months preceding admission (alcoholics) or testing (controls). QFI = Quantity-Frequency Index based on 100% ethanol consumed in ounce per day for all alcoholic beverages combined. WAQ = Withdrawal Assessment Questinnnaire total severity score. *p < 0.05, "tp < 0.001.

were referenced to concentrations of creatinine, taking into account differences in urine production and collection time intervals. The reliability of using urine samples for cortisol measures has been established (18).

Alcohol and Nicotine Use Duration and quantity of alcohol abuse and nicotine use were obtained by interview. Quantity and frequency of wine, beer, and liquor consumption for the 6 months preceding admission were assessed by a structured interview of alcohol drinking patterns (7). These estimates were converted to an overall q u a n t i t y - f r e q u e n c y index of ounce of 100% ethanol consumed per day (17). Withdrawal severity was assessed by our modified version of the Clinical Institute Withdrawal Assessment ( C I W A ) (28), an interview designed to quantify physiological and perceptual changes experienced during withdrawals. W e used 15 items coded on 4-point scales of increasing severity to develop a total withdrawal assessment score for severity of withdrawal symptoms. Items pertained to a patient's recall of symptoms experienced during the first 24 h after a typical cessation of drinking.

Statistical Analyses Subject characteristics and psychosocial variables were analyzed across groups by one-way analyses of variance ( A N O V A ) . Cortisol levels and subjective responses were analyzed by r e p e a t e d - m e a s u r e s A N O V A with G r o u p (alcoholic and control) serving as the between-subjects factor and T i m e

(baseline and posttask) as the repeated measure. Significant main effects or interactions were followed by simple effects tests. Pearson p r o d u c t - m o m e n t correlations were used to test the relationship between the cortisol data and the various psychological and physiological factors examined. Standard multiple regression analyses were carried out using drinking, health and demographic variables to predict cortisol posttask.

RESULTS There were no significant differences between alcoholics and controls (Table 1) in age, educational level, or verbal intelligence, as estimated by the Shipley Institute of Living Vocabulary Age score (29). Cortisol levels for all subjects were in the normal range. The groups had differential cortisol responses to the stressors as indicated by a significant G r o u p × T i m e interaction, F(1, 52) -- 4.28, p < 0.05. Simple effects tests showed that the groups did not differ at prestress baseline, F(1, 52) = 1.84, p = NS. The poststress values, however, showed that alcoholics were significantly lower than the controls, F(1, 52) = 5.42, p < 0.05 (see Fig. 1). This indicates an attenuated response to the tasks by the alcoholics. As expected, the alcoholics reported using significantly more nicotine (Table 1) than did the controls, F(1, 51) = 13.54, p < 0.001, and more symptoms of depression and anxiety at the time of testing [BDI, F(1, 52) = 5.46, p < 0.05; SAIT, F(1, 52) = 7.94, p < 0.001]. H o w e v e r , the symptoms were at subclinical levels. The attenuated poststress cortisol levels among alcoholics do not appear to be a function of psychological re-

496

B E R N A R D Y ET AL. ug/mg Cre

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CONTROLS

ALCOHOLICS

F I G . 1. Baseline and poststress urinary cortisol levels for alcoholics (n = 40) and nonalcoholic controls (n = 14). Values p r e s e n t e d are m e a n s + SEM.

sponses during testing because the alcoholics and controls described similar levels of subjective distress, F(1, 52) = 2.36, p = 0.13, and activation, F(1, 52) = 1.74,p = 0.19, to the stressors. Turning to drinking parameters, the withdrawal severity score had a marginally significant positive relationship with post stress cortisol levels (r -- 0.30, p = 0.06). The total withdrawal severity score was not related to baseline cortisol levels (r = 0.20, p = NS). Standard regression analyses using drinking, withdrawal, health, and demographic variables to predict poststress cortisol levels showed that the total withdrawal assessment score for severity of withdrawal symptoms was the most predictive of the variables studied (R 2 = 0.10, F = 2.42, p = 0.06). The other potential confounds, such as nicotine use, liver function, age, affective state measures, or task perception, did not significantly improve prediction of poststress cortisol values. Family history of alcoholism was not related to cortisol levels and did not contribute significantly when added to the prediction equation. Finally, although patients were free from liver disease, subclinical liver function alterations, as measured by admission levels of serum glutamic-oxaloacetic transaminase (SGOT), also did not predict cortisol response (R 2 = 0.02, p =

TABLE 2 CORRELATION BETWEEN CONSUMPTION VARIABLES AND CORTISOL POSTSTRESS CONCENTRATIONS AMONG ALCOHOLICS Variable

WAQ total score QFI Lifetime nicotine use

r

p

0.30 0.30 0.27

0.06 0.06 0.10

Entries show Pearson's r and significance levels. WAQ - Withdrawal Assessment Questionnaire. QFI = Quantity-Frequency Index of total alcohol consumption. Lifetime nicotine use - number of cigarettes reported smoked daily × chronicity of years smoked. N 40.

DISCUSSION

Relative to controls, the abstinent alcoholics displayed an attenuated urinary cortisol response to the stressors, supporting the blood cortisol findings of Margraf (21) and Errico (11). The patients' diminished poststress cortisol levels do not appear to be influenced by anxiety, depressive symptoms, task perception, or other potential confounds such as age, nicotine use, or liver function. It appears that the alcoholics' attenuated response may reflect an alteration in the ability of the H P A C axis to react to sudden demands. Work by Adinoff et al. has indicated that altered H P A C function may persist at 3 weeks abstinence, with more subtle impairments noted for longer than 6 months (1). Our data demonstrating diminished stress levels to biobehavioral stressors after three to four weeks of sobriety support these findings. The alcoholics showed a normal prestress value comparable to that shown by the controls. We have previously reported similar baseline cortisol levels in controls and alcoholics who were 1-month sober (11). These comparable prestress cortisol values suggest maintenance of a normal circadian rhythm in the alcoholic patients. Although the alcoholics as a group had attenuated cortisol responses to stress, the highest poststress values occurred in patients reporting the most severe withdrawal symptoms. This relationship between H P A C axis activity and withdrawal signs has been reported by others (1,2,15). Although prior studies made simultaneous measures of cortisol and withdrawal symptoms, we found this relationship using retrospective withdrawal data. Our finding of a greater cortisol stress responsiveness at 3-4 weeks in patients with more severe withdrawal symptoms provides an extension of Adinoff's (2) results. It appears a subset of these patients is showing extended consequences of chronic consumption beyond an acute withdrawal phase. This heightened cortisol response, along with other physical signs of protracted withdrawal associated with greater relapse risk (26), together may provide a useful clinical measure of relapse susceptibility. The finding that alcoholics as a group have diminished responses appears contradictory to greater poststress levels in patients with the worst reported withdrawals. Those alcoholics with elevated cortisol responses and the most severe withdrawal symptoms may have an inherently increased H P A C stress responsiveness, which could be a contributing factor to the dysphoria and symptoms of withdrawal. A relationship between premorbid glucocorticoid dynamics and withdrawal responses has been demonstrated in animal research (2325,31). Differences in cortisol response to an ethanol challenge have been demonstrated in individuals with a positive family history of alcoholism compared to those with negative family history (14,27), suggesting that humans also show genetically determined differences in H P A C activity. A major problem of this research has been separating differences initially influenced by genetic factors from those related to individual consumption patterns or withdrawal effects. Although we were unable to test such premorbid factors due to a majority of family history positive alcoholics (i.e., 82%), a familial transmittance of H P A C responsiveness cannot be ruled out. Concerning methodological issues in this study, cortisol may be sampled from blood, urine, or saliva with each sample source providing a different view of H P A C function. The majority of studies thus far has used repeated blood sampling.

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This method, however, is invasive, and may cause additional stress and alteration of H P A C axis activity. Additionally, plasma samplings reflect both b o u n d and unbound cortisol fractions. Advantages of urinary cortisol measures include that they reflect only the unbound concentration, are not influenced by variations in serum protein binding, are thought to be proportional to free cortisol in blood (18), and reflect the s u m m e d activity over the time of collection. Thus, changes in concentration seen in the poststress sample indicate the degree of activity both during and immediately after the application of the stressors. The values obtained here therefore reflect diurnal and stress-related secretion of cortisol uncomplicated by the stress of venipuncture. In sum, these data using urinary samples support other work showing altered H P A C function in alcoholics. The mechanisms underlying these alterations are not known, but the depressed function in the group as a whole and the elevated function in those with more severe withdrawals present interesting problems for future research. On the one hand, failure of the H P A C axis to respond to stress with adequate secretion of glucocorticoids can lead to negative conse-

497 quences, including tissue damage (22). The alcoholics' depressed secretion of cortisol may therefore not be benign. O n the other hand, the patients showing elevated cortisol values and exaggerated withdrawal symptoms may represent a special group requiring m o r e refined studies. In particular, the relation between severe withdrawal symptoms and an increased relapse risk to alcohol should be explored. Further research should continue to examine the relationship of drinking variables and withdrawal symptomatology to glucocorticoid levels during acute withdrawal and the issue of recovery of H P A C function with longer periods of abstinence.

ACKNOWLEDGEMENTS Supported by Medical Research Service of the Department of Veterans Affairs and National Institute on Drug Abuse Grant #DA05448. We wish to thank the staffs of the Veterans Affairs Medical Center Chemical Dependency Unit and the Norman Alcohol and Drug Treatment Center. Appreciation is also expressed to Dr. Terry McDowell, Megan R. Lerner, and Jack Shepard for assistance with the cortisol determinations.

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