Basal and post-dexamethasone cortisol and prolactin concentrations in depressed and non-depressed patients with chronic pain syndromes

23

Pain, 25 (1986) 23-34 Elsevier

PAI 00868

Basal and Post-Dexamethasone Cortisol and Prolactin Concentrations in Depressed and eon-Depressed Patients with Chronic Pain Syndromes Joseph H. Atkinson, Jr. 1*2,Edwin F. Kremer 2, Samuel C. Risch ’ and David S. Janowsky 2 ’ Department of Psychiatry (V-I I6), Veterans Administration Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, and ’ Department of Psychiatry (M-003), University of California San Diego, School of Medicine. Lu Jolla. CA 92093 (U.S.A.) (Received

9 November

1984, revised received 5 September

1985, accepted

10 September

1985)

Summary

To assess the behavior of two putative neuroendocrine markers of depression in chronic pain, the authors determined plasma cortisol and prolactin concentrations before and after dexamethasone in 52 hospitalized male chronic pain patients. Their psychiatric diagnoses by Research Diagnostic Criteria (RDC) were: major depression (N = 24; 44.2%), minor depression (N = 10; 19.2%), another RDC diagnosis (N = 7; 13.5%) and not mentally ill (N = 12; 21.6%). Failure to suppress cortisol after dexamethasone (a positive DST) occurred in 43.5% of those with major depression, 20% of those with minor depression, 42.8% of those with other psychiatric diagnoses and in 8.3% of patients without a psychiatric disorder. The frequency of non-suppression was significantly different only for patients with major depression compared to those without diagnosable psychiatric disorder. Mean basal cortisol concentrations at 08.00, 16.00 and 23.00 h did not differ among psychiatric diagnostic groups of pain patients, or between these groups and healthy volunteers. Levels of prolactin, but not cortisol, were significantly correlated with the severity of mood disturbances. These findings suggest strategies using multiple endocrine markers to distinguish pain from depression should be explored.

Reprint

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0304-3959/86/$03.50

to: J.H. Atkinson,

Jr., M.D.

0 1986 Elsevier Science Publishers

B.V. (Biomedical

Division)

24

Introduction The reported incidence of depression in chronic pain varies from 10% to almost 90% [26,2X$38,45] and encompasses a broad range of severity of affective disturbance. Because affective disorder is associated with considerable morbidity and may interfere with pain rehabilitation 1371 its detection is important. Adrenal cortisol hypersecretion, flattened cortisol circadian periodicity, and failure to suppress plasma cortisol concentrations following administration of exogenous steroid (an abnormal or positive dexamethasone suppression test, (DST)) have been consistently observed in a substantial proportion of depressed psychiatric patients [9,‘10]. Patients with other psychiatric illnesses may have an abnormal DST [4,16] and there is concern that cortisol non-suppression is not specific for affective disorder. Additi~naI neur~ndocrine response abnormalities have been noted in depressed patients [8,39,49], including disregulation of prolactin secretion [15,36] and failure of dexamethasone to suppress plasma prolactin levels in those patients who fail to suppress cortisol[35]. With regards to pain syndromes, Lascelles et al. [29] concluded that mean cortisol levels were elevated in organic and psychogenic pain states compared with normal group means, and that diurnal variation of cortisol was diminished in both categories. By contrast, Shenkin [43] reported that patients with psychogenic pain had both normal mean levels of cortisone and normal diurnal periodicity, but that those with somatic pain had elevated cortisol and flattened periodicity. More recently, non-suppression of cortisol following dexamethasone has been reported in psychogenic pain disorder [7], and in depressed back pain patients [20]. These reports did not assess prolactin secretion. The purpose of this study was to further investigate the relationship of basal and post-dexamethasone cortisol and prolactin concentrations to affective disorder in chronic pain patients rigorously evaluated for psychiatric illness. Chronic pain was defined as pain on a daily basis for 6 months or longer, mood was assessed by standardized rating scales, and psychiatric diagnosis was established by Research Diagnostic Criteria (RDC) [43] and the criteria of the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) [2].

Subjects Fifty-two male pain patients consecutively admitted to the inpatient pain treatment program at the San Diego Veterans Administration Medical Center gave informed consent to the study. The mean age was 55.4 years with a range of 34-82 years. The mean ( & S.D.) duration of chronic pain was 17.9 ( + 13.4) years with a range from 6 months to 44 years. The sites of pain complaint were back and neck 74.1%, extremity 20.2%, and other sites, 5.7%. The medical diagnoses were chronic pain from degenerative disorder of the spine (intervertebral disc disease, spondylosis.

25

osteoarthritis) (48.1%); or from injury (lifting, etc.) or surgery performed for degenerative disorder (34.6%); neuropathic syndromes (9.4%); and renal stones (1.9%). Many patients had at least one surgery related to their presenting pain complaint (44.2%) and the mean number of surgeries was 2.04. A substantial proportion of patients (57.3%) had a history of multiple pain problems, defined as chronic pain in a site different from their presenting complaint which had interfered with function or caused them to seek medical attention. No patient had an acute medical illness associated with non-suppression of cortisol after dexamethasone, and no medications enhancing dexamethasone metabolism were being administered. At the time of the dexamethasone suppression test, patients had been started on the following medications: non-narcotic analgesics (73.1%); codeine (15/3%); antidepressants (38.9%), or benzodiazepines (37.9%). The analgesics were: aceta~nophen (N = 26), indomethacin (N = 2), baclofen (N = I), ibuprofen (N = 3) zomepirac (N = 5), napronen (N = 2), and codeine (N = 8); the psychotropics were: diazepam (N = 7) flurazepam (N = 8). chlordiazepoxide (N = l), lorazepam (N = 1); amitriptyline (N = 9) doxepin (N = 2), amoxapine (N = 3) protriptyline (N = l), maprotiline (N = 3), trazodone (N = 2); chlorpromazine (N = l), and thiothixene (N = 1). Sixteen healthy male volunteers served as a comparison group for basal cortisol concentrations. Their mean age (26.1 + 5.7 years) was significantly less than that of pain patients (t = 14.65, P < 0.001).

Procedure

On admission each pain patient was evaluated by a psychiatrist, a psychologist, and a neurosurgeon. Before the study began a psychiatric diagnosis was made by the relevant clinicians and by an experienced psychiatric diagnostician according to Research Diagnostic Criteria. Patients with a recognizable psychiatric disorder not described under RDC diagnoses were classified as ‘other RDC,’ and in accordance with established guidelines were diagnosed using DSM-III criteria. Medical diagnoses were provided by the referring physician and the pain unit neurosurgeon. RDC considers symptoms to have psychiatric diagnostic significance only if they are severe enough to have clinical importance and yet are not attributable to a physical cause. RDC depressive symptoms which the attending neurosurgeon attributed to physical illness were excluded from contributing toward a psychiatric diagnosis. At the end of the second week of hospitalization an overnight DST was performed according to accepted procedures [lo]. Dexamethasone 1 mg was administered orally between 23.00 and 24.00 h on day 1 and samples for serum cortisol and prolactin were obtained at 08.00, 16.00, and 23.00 h on days 1 and 2. On day 1 an investigator who was unaware of the patient’s diagnosis administered the Beck Depression Inventory [S] and the 21-item Hamilton Rating Scale for Depression (HRSD) 121J.

Tests Neuroendocrine assays Serum cortisol was measured by radioimmunoassay using “‘I-antibody (Rianen Assay System, New England Nuclear, North Billerica, MA). The range for healthy volunteers was 7-25 pg/dl. The interassay coefficient to variation was less than 10% and in&a-assay coefficient of variation ranged from 1% to 10% for the low, medium, and high ranges of the cortisol curve. Non-suppression was defined as any post-dexamethasone plasma cortisol level of 5 pg/dl or greater. Prolactin was determined by radioimmunoassay using ‘251-antibody (Immunex, San Diego, CA). The sensitivity of the assay was 2 ng/ml. All samples were measured in the same assay, and the intra-assay coefficient of variation was less than 10%. The range for healthy adult men was 5-20 ng/ml. No patient had an 08.00 h predexamethasone prolactin concentration greater than 20 ng/ml. Because codeine, neuroleptics, trazodone, and amoxapine are reported to stimulate prolactin secretion 133,411 patients (N = 13) taking these agents were excluded from analysis of prolactin data, as were patients (N = 11) with missing data. Statistical ana&sis Continuous variables were analyzed using the Biomedical Computer Program Series - P programs for analysis of variance (ANOVA) [18]. BMDP-PlD calculations of skewness and kurtosis exceeded the accepted limits of normality for cortisol and prolactin values so these data were analyzed after logarithmic transformation. The frequency of non-suppression after dexamethasone was assessed using Fisher’s exact probability, accepting P values of less than 0.05 as significant. Associations among cortisol and prolactin concentrations were determined using Pearson’s r correlations.

Results Table I presents the psychiatric’characteristics of study patients. Twelve patients (21.6%) were not psychiatrically ill. Thirty-three patients (63.4%) met RDC criteria for either a major or minor depressive disorder and 7 (13.5%) had another RDC or DSM-III psychiatric diagnosis. In Table I these ‘7 patients were categorized as mixed RDC. Their diagnoses were schizoaffective disorder, depressed (N = 1); alcoholism, post-withdrawal (N = 1); organic mental state (dementia) (N = 2); and mixed personality disorder (N = 3). Analysis of variance demonstrated significant differences among the diagnostic groups for Beck (F (3, 48) = 3.13, P < 0.05) and Hamilton (F (3, 48) = 4.32, P -c0.01) scores. Pairwise comparisons revealed a reliably higher score on the Beck for those with major depression vs. mixed RDC (t = 2.78, P < 0.011, and on Hamilton scores for major depression vs. both mixed RDC (t = 2.71, P < 0.01) and the not mentally ill (I = 2.91, P < 0.01). No other differences were reliable. Table II presents the major results of the experiment. Applying the accepted

27 TABLE

I

PSYCHIATRIC DIAGNOSIS PAIN PATIENTS

AND

RDC diagnosis Major depressive

disorder

Minor depressive disorder Mixed psychiatric disorders Not mentally ill

DEPRESSION

RATING

INVENTORIES

IN 52 CHRONIC

N

x

Hamilton

score (S.D.) *

23

44.2

24.82 a.b

(13.93)

Beck Inventory 17.00 f

10 I 12

19.2 13.5 21.6

22.21 10.74 11.8

(15.5) (8.40) (7.8)

11.9 7.00 11.9

(S.D.) ** (7.60)

(4.3) (8.19) (11.5)

* F (3, 48) = 44.32, P <:0.01. ** F (3, 48) = 3.12, P c 0.05. ilt= 2.71, P < 0.01 compared to mixed RDC. ’ t = 2.91, P c 0.01compared to not mentally ill. ’ r = 2.78, P < 0.01, compared to mixed RDC.

criterion for non-suppression [ll] as any post-dexamethasone cortisol level of 5 pg/dl or more revealed that 16 pain patients (30.8%) failed to suppress cortisol. Non-suppression was more common in pain patients with major depression (43.5%)

TABLE

II

CORTISOL CONCENTRATIONS TIENTS AND CONTROLS Cortisol nonsuppression

Group

Major depression (N = 23) Minor depression (N = 10) Mixed RDC (N = 7) Not mentally ill (N =12) Healthy volunteers (N = 16)

BEFORE

AND

AFTER

DEXAMETHASONE

IN

PAIN

PA-

Mean (S.D.) cortisol (gg/dl) *

Pre-dexamethasone

N

%

08.00 h

10

43.5 **

2 3 1

Post-dexamethasone

16.00 h

23.00 h

08.00 h

16.00 h

23.00 h

15.8 (5.4)

9.7(3.4)

6.1 (5.7)

3.8(3.3)

3.7 (3.1)

3.4(2.4)

20.0 42.8

14.5 (9.3) 15.5 (8.4)

8.1 (6.9) 7.9(4.2)

4.3(2.0) 4.3(2.5)

2.7(1.1) 2.5 (1.4)

2.6(1.5) 4.2(3.1)

2.3 (0.7) 3.6(2.0)

8.3

12.5 (3.9)

6.712.3)

4.3 (2.2)

3.7 (5.7)

2.5 (1.5)

2.4f0.9)

-

_

17.4 (4.8)

8.7 (3.2)

-

-

-

_

-

-

12.8 (4.5)

7.1 (2.7)

5.2(4.9)

2.2(0.4)

2.1 (0.2)

2.1 (0.3)

-

-

19.2 (7.8)

4.9 (1.9)

6.2 (5.5)

6.1 (3.2)

4.9 (2.5)

Cortisol suppressors Cortisol nonsuppressors

***

11.6(5.4)

* Maximum post-dexamethasone cortisol values (pg/dl) for non-suppression were: major depression (5.3, 6.0, 6.7, 8.2, 9.6, 10.4, 11.1, 12.3, 13.2, 14.0); minor depression (5.0, 6.6); mixed DC (6.8, 7.5, 9.3); not mentally ill (21.9). ** Significantly higher than group not mentally ill, P < 0.04. *** Mean basal cortisol concentrations significantly higher than suppressors, P < 0.004.

28

and minor depression (20%) than in those not mentally ill (8.3%). Yet 3 of the 7 patients (42.8%) in the mixed RDC category also failed to suppress cortisol. The diagnoses of these 3 non-suppressors were schizoaffective disorder, depressed (N = 1) and organic mental state (dementia) (N = 2). The frequency of non-suppression was reliably different only between the major depression and the not mentally ill groups (Fisher’s exact test, d‘= 1, P < 0.04). There was no significant difference in frequency of non-suppression among pairwise combinations of the other diagnostic groupings. There was no reliable difference in severity of mood disturbance between suppressors and non-suppressors on Beck (F (I, 49) = 3.75, P > 0.06) or Hamilton ratings (F (1,49) = 0.12, P > 0.50). There was also no difference in the mean age ( F S.D.) of suppressors and non-suppressors (55.4 years (+ 11.4) and 56.5 years (& 11.8) respectively). Because the DST was performed during the second week of hospitalization it is less likely that elevated cortisol levels were simply a response to a novel stress such as hospitalization. To examine whether recent pain onset, or recent injury or surgery predicted cortisol non-suppression, separate stepwise multiple logistic regression analyses (BMDP-LR) were performed using pain chronicity (approximate F to enter = 1.70) and length of time since most recent injury or surgery (approximate F to enter = 1.14). The probability attached to both chronicity and time since surgery/injury was not significant. Similar effects were obtained when only patients with major depression were considered. It should be noted, however, that overall only 7% (3/42 patients) had surgery or an injury within 1 year or less, so the sample was highly biased for remote injury or intervention. Furthermore, relatively few patients (9/52, 17%) had pain of 5 years duration or less. With regard to medications, there was no difference between plain and pain-major depression groups in the frequency of use of no analgesics (8.3% pain only vs. 8.3% pain-major depression), non-steroidal anti-inflammatory analgesics (75% vs. 68%). codeine (8.3% vs. 12.5%) and benzodiazepines (33.3% vs. 41.6%) (all PS > 0.10; Fisher’s Exact test). Fifteen (62.5%) of the pain-major depression group were receiving cyclic antidepressant vs. one (8.3%) in the pain-no psychiatric diagnosis group (P < 0.002). We also assessed whether presence or absence of classes of medication (antidepressants), benzodiazepines, codeine, or non-steroidal anti-inflammatory analgesics) or combinations of classes predicted a significant amount of variance in cortisol suppressor/non-suppressor status. Stepwise logistic regression (approximate F to enter = 2.18) failed to indicate a significant effect of medication status on result of the DST. Table II also presents the mean (kS.0.) cortisol concentrations for healthy volunteers and the psychiatric diagnostic subcategories of pain patients. A one-way ANOVA of 08.00 and 16.00 h basal cortisol concentrations did not disclose a reliable overall difference between healthy volunteers and the pain patients (F (4. 63) = 2.07, P > 0.10). A group (psychiatric diagnosis) X trial (pre-dexamethasone, post-dexamethasone) x time (O~.~, 16.00 23.00 h) repeated measures ANOVA revealed that cortisol concentrations at each sampling time before and after dexamethasone did not differ reliably overall among major depression minor depression, other psychiatric diagnosis, and not mentally ill pain patients (F (3.

29

TABLE

III

PROLACTIN PATIENTS *

CONCENTRATIONS

BEFORE

Mean (S.D.) prolactin

Group

Major depression (N = 10) Minor depression (N = 4) Mixed RDC (N = 3) Not mentally ill (N = 11) Cortisol non-suppressors (N = 9) Cortisol suppressors (N = 19)

AND

AFTER

(q/ml)

DEXAMETHASONE

IN 28 PAIN

**

Pre-dexamethasone

Post-dexamethasone

08.00 h

23.00 h

08.00 h

16.00 h

23.00 h

8.6 7.2 6.5 8.5

(3.7) (3.1) (1.3) (2.2)

8.8 (2.4) 10.2 (5.1) 6.4(2.0) 10.3 (3.6)

24.8 (43.6) 11.0 (4.6) 13.6 (5.7) 11.8 (5.2) 12.9

16.00 h

11.0 (3.7) 8.1 (2.7)

9.7 (4.3) 7.2 (1.6)

8.4 (1.5) 9.0 (2.6)

10.6 (1.1) 10.4 (3.1)

15.3 (14.3) 8.4 (3.0) 1.05 (4.5) 9.8 (2.7)

10.1 (3.0)

10.9 (3.8)

16.7

(14.6)

9.9 (3.7)

10.8 (3.9)

9.3 (3.2)

9.0 (3.0)

9.2

(2.6)

1.1 (2.3)

8.6 (3.0)

(6.5)

18.5 (32.5)

* Excludes those pain patients taking medications **

known to stimulate prolactin secretion (neuroleptics, trazodone, amoxapine, or codeine). Significant effect of time (F = 14.1, df = 2.26, P < 0.~1). with 23.00 h concentration reliably higher than 08.00 h (paired I = 3.89, P i 0.001) and 16.00 h (paired t = 2.74, P < 0.01). No significant effect of diagnostic group. trial, or group x time interaction.

48)= 2.05,P > 0.10). There was a significant trial effect (F (1,48)= 238.78, P -cO.OOl), reflecting dexamethasone suppression of cortisol concentrations. As expected a trial x time interaction was also significant (1" (2,47) = 51.93, P -e0.0001). Baseline day cortisol levels overall were significantly higher in cortisol non-suppressors than in cortisol suppressors (F (1, 50) = 9.24. P < 0.005). In patients with major depression, however, basal cortisol concentrations did not differ between suppressors and non-suppressors. As shown in Table III, the response of prolactin to dexamethasone and the

TABLE

IV

PRE-DEXAMETHASONE PROLACTIN CRITERION CONCENTRATIONS TIATE DEPRESSED AND NON-DEPRESSED PATIENTS 08.00 h criterion

*

(ng/mI)

Pain Pain-major

depressions

16.00 h criterion

**

(ng/mI)

WHICH

DIFFEREN-

23.00 h criterion

***

(ng/mI)

I12.00

> 12.0

5 16.0

> 16.0

511.0

> 11.0

9 2

2 10

10 6

1 6

9 3

2 7

* P = 0.003. ** P=O.O4. *** P = 0.02. g Sample size varies because

of missing points at 23.00 h.

30

association of cortisol non-suppression and prolactin non-suppression was examined using the method of previous reports [34]. After excluding patients on neuroleptics, amoxapine, trazodone, and codeine, as well as those with any missing data, prolactin concentrations were compared in cortisol suppressors (N = 19) and the non-suppressors (N = 9). For prolactin concentrations a group (cortisol suppressors, non-suppressors) X tria1 (predexamethasone, post-dexamethasone) x time (08.00. 16.00, 23.00 h) repeated measures ANOVA did not demonstrate a significant effect for group (I; (1, 27) = 2.47, P > O.lO), or a group x trial interaction ( F (1, 27) = 0.47, P > 0.50). The association of prolactin and cortisol concentrations was analyzed using Pearson’s correlations. There was no significant correlation at any time interval between prolactin and cortisol concentration. Changes in prolactin and cortisol concentrations at each sampling time (pre-dexamethasone concentration minus post-dexamethasone concentration) were similarly analyzed. Again, there were no significant correlations at any time point. The prolactin concentrations were not normally distributed. Therefore, simiiar to the approach used to identify the cortisol criterion value for the DST, a computerized program derived from Fisher’s Exact test also was employed to begin to explore whether ‘cut-points’ of prolactin significantly differentiated nosological groups of patients. A pre-dexamethasone prolactin ‘cut-point’ of 12.0 ng/ml at 08.00 h best discriminated depressed from not psychiatrically ill subjects (Table IV). No post-dexamethasone values reliably differentiated these groups. Finally, we examined the correlation between endocrine variabIes and severity of mood disturbance. As shown in Table V, multiple linear regression coefficients were determined for cortisol (N = 52 patients) and prolactin (N = 28 patients) concentrations and scores on the Hamilton and Beck depression inventories. Baseline and post-dexamethasone prolactin concentrations were positively and significantly correlated with Hamilton scores and accounted for approximately 13-21s of the variTABLE

V

MULTIPLE LINEAR REGRESSION COEFFICIENTS (expressed as T’) FOR PROLACTIN CONCENTRATIONS AND SCORES ON HAMILTON RATING PRESSION AND BECK DEPRESSION INVENTORY Hamilton

Rating

Beck Depression

Scale

Cortisol (N = 52)

Prolactin (N = 28)

Cortisoi (N = 52)

CORTISOL AND SCALE FOR DE-

Inventory Pro&tin (N = 28)

r2

P

2

P

2

P

2

P

Pre-dexamethasone 08.00 h 16.00 h 23.00 h

0.07 0.0004 0.002

0.17 0.91 0.83

0.20 0.04 0.13

0.01 0.28 0.05

0.001 0.03 0.009

0.86 0.32 0.61

0.005 0.02 0.09

0.72 0.41 0.11

Post-dexamethasone 08.00 h 16.00 h 23.00 h

0.04 0.00s 0.005

0.27 0.7 0.7

0.13 0.13 0.21

0.05 0.05 0.01

0.05 0.03 0.07

0.23 0.30 0.14

0.05 0.04 0.02

0.22 0.32 0.51

31

ante. Cortisol and prolactin levels were not correlated with Beck scores; cortisol values were not correlated with Hamilton scores at any time point.

similarly

Discussion The major findings of this study were that: (1) a high percentage of chronic pain patients with major depression as well as with other mental disorders showed resistance to dexamethasone suppression of cortisol; (2) non-suppression discriminated only pain patients with concurrent major depression from those without a psychiatric diagnosis; and (3) that there was an association between plasma prolactin concentrations and observer-rated severity of depression. The percentage of pain patients with major depression who failed to suppress cortisol was similar to that reported for psychiatric patients hospitalized for major depression [lo], as well as for low back pain patients with major depression [20]. The percentage of pain patients without a psychiatric disorder showing non-suppression was in the range of 3-15% reported for healthy volunteers [3,42,49] and is consistent with the low frequency of non-suppression reported for other chronic pain populations without psychiatric illness [23]. It would appear then that chronic pain itself does not result in non-suppression of cortisol. The high frequency of non-suppression in pain patients with a major psychiatric disorder and the prevalence of psycholo~cal disturbance in chronic pain populations [27] argue against the use of the DST alone to detect depressive illness in this population. It has been reported that factors such as onset of illness within 1 year and greater functional disability appear to interact with depressed mood to cause abnormal DSTs [29]. While we did not demonstrate that pain chronicity or time since injury of surgery contributed to cortisol non-suppression, these factors may be potent in populations with shorter duration of pain, or more recent surgery. We were unable to confirm the report that, overall, pain patients have higher basal cortisol levels and flattened diurnal periodicity compared to normal subjects [43]. Differences in age and activity levels between our controls and pain patients may account for our finding. Yet the original report [43] included subjects with acute pain, who might have different cortisol secretory patterns than chronic pain patients. It also should be noted that our own data and previous work [29,43] observed wide variability in cortisol concentrations. Given the pulsatile nature of cortisol secretion studies using continuous plasma sampling may be required to resolve questions of group differences. This study supports previous work indicating that depressed mood may be associated with abnormalities in prolactin regulation 115,361. This study is also consistent with reports [25] that prolactin concentrations are correlated with Hamilton ratings of depression. The failure of neuroendocrine variables to correlate with Beck depression scores is consistent with reports that pain patients deny or are reluctant to admit psychological distress. The Hamilton may be a more sensitive in such instances because observers could rate distress which the patients might deny or dismiss on self-report instruments.

32

We did not find an association between non-suppression of cortisof and non-suppression of prolactin [34]. Non-suppression of prolactin may be associated with post-dexamethasone cortisol in excess of 1.5 pg/dl [24] and our failure to note this effect may be related to modest post-dexamethasone cortisol concentrations. Also, prolactin responses to neuroendocrine challenge may differ between male and female subjects [SO]. We studied men, while Meltzer et al. [35] do not state the sex distribution of their sample. The results of this study also must be considered in the context of medications prescribed at the time of testing. First, prostaglandins (PC) may be involved in the regulation of the hypothalamic-pituitary-adrenal axis [ 17,221, and inhibitors of PG synthesis, such as non-steroidal anti-inflammatory agents could alter cortisol secretion. Studies in normal subjects to date indicate that these agents in clinical dosages do not alter the diurnal pattern of cortisol secretion or its response to dexamethasone, metyrapone, or to ACTH stimulation 16,111. Studies in depressed patients report that at least one non-steroidal agent (indomethacin) can produce a false-negative DST by converting a non-suppressor into a suppressor ]32]. Although these agents may have affected prolactin reiease, no known reports bear on this question. With regards to other agents, most evidence indicates that benzodiazepines in modest dosages have no effect on basal cortisol concentrations or produce only temporary suppression in animals [30] and man [46,48], although very high dose benzodiazepines may reverse dexamethasone non-suppression. Tricyclic antidepressants and neuroleptics at steady-state levels are not believed to alter cortisol response to dexamethasone [to], and neither tricyclics [34] nor benzodiazepines [13,27] appear to affect prolactin secretion. Endorphinergic mechanisms may be altered in chronic pain and in depression [1,14] and endogenous opioid peptides are known to regulate prolactin and other anterior pituitary hormone secretion by increasing or attenuating turnover of hypothalamic neurotransmitters [19,40,47]. Thus, investigating the behavior of multiple biological markers, at basal conditions and after neuroendocrine challenge, may help distinguish pain, depression, and other psychiatric disorder.

Acknowledgements This research was supported in part by National Cancer Institute Contract NOl-CN-85417-06 and NIH Grant MH30914. The authors gratefully acknowledge the assistance of Joan Mitrea, R.N., Pattie L. Krohn and Gus Griffin.

References 1 Aimay, B.G.L.. Johansson. F., van Knorring, L., Terenius, L. and Wahistr(im, A., Endorphins chronic pain. I. Differences in CSF endorphin levels between organic and psychogenic pain dromes, Fain. 5 (1978) 153-162.

in syn-

33 2 American

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and Statistical

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of Mental

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