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beta-lipotropin-like immunoreactivity in chronic pain syndrome and psychiatric subjects
Psychiarry Research. 9, 3 19-327
319
Elsevier
of Plasma Measures Like lmmunoreactivity Psychiatric Subjects
Beta-Endorphin/Beta-Lipotropinin Chronic Pain Syndrome
and
Joseph H. Atkinson, Edwin F. Kremer, Samuel C. Risch, Charles Morgan, Raana Fryer Azad, Cindy L. Ehlers, and Floyd E. Bloom Received
March
10, 1983: revised
version
received
July 15, 1983; accepted
D.
July 25, 1983.
Abstract. This study compared basal concentrations of plasma B-endorphin/Plipotropin-like immunoreactivity and dexamethasone suppression of cortisol in seven chronic pain patients, seven psychiatric disorder patients, and seven normal volunteers. Pain patients and psychiatric patients showed significantly higher basal concentrations of /3-endorphin/a-lipotropin-like immunoreactivity compared to normal volunteers. Pain patients also had significantly higher P-endorphin//S lipotropin-like immunoreactivity than psychiatric patients, even though there was no significant difference in severity of depressive symptomatology as assessed by Beck and Hamilton scores. Resistance to dexamethasone occurred in 57% of pain patients. These results may indicate that biological markers for depression occur in populations of chronic pain patients, or may reflect levels of central nervous system arousal in response to stress, pain, or nonaffective phenomena. Key Words. /3-Endorphin//_Uipotropin-like suppression test, chronic pain, depression.
immunoreactivity,
dexamethasone
P-Endorphin is thought to be involved in the mediation of pain perception. Several groups also have shown that P-endorphin is increased acutely by stress in animals (Guillemin et al., 1977a) and man (Morley and Levine, 1980; Cohen et al., 1981; Dubois et al., 1981), as is adrenocorticotropin (ACTH) (Guillemin et al., 1977b) and fi-lipotropin (b-LPH) (Gilkes et al., 1975). Therefore, an elevated concentration of /3-endorphin may reflect the body’s response to acute pain or stress. Other preliminary evidence indicates, however, that P-endorphin may be related to psychiatric symptomatology. Risch (1982) noted that morning plasma concentrations of P-endorphin/Plipotropin-like immunoreactivity detected by radioimmunoassay were significantly higher in a group of depressed patients meeting Research Diagnostic Criteria (RDC) (Spitzer et al., 1977) for major depressive disorder or schizoaffective disorder, depressed, than in groups of normal volunteers and psychiatric patients without affective disorders. A radioreceptor assay plus fractionation used by Terenius et al.
Joseph H. Atkinson, Jr., M.D., Edwin F. Kremer, Ph.D., Samuel C. Risch, M.D., Charles D. Morgan, M.D., and Cindy L. Ehlers. Ph.D.,are in the Department of Psychiatry(M-O03), University of Californiaat San Diego School of Medicine, La Jolla, CA 92093, USA. Raana Fryer Azad, M.S., and Floyd E. Bloom, M.D.. are at the Salk Institute of Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. (Reprint requests to Dr. J.H. Atkinson, Jr.) 01651781:83~$03.00
@ 1983 Elsevier Science Publishers
B.V.
320 (1977) to assess opioid peptides intermediate in size between met-enkephalin and /I-endorphin detected elevated fraction I endorphins in depressed patients. This group also noted that concentrations of fraction I endorphins isolated from cerebrospinal fluid (CSF) were jiositively correlated with depressive symptomatology in chronic pain patients, and were significantly higher in patients with predominantly psychogenic chronic pain than in those with predominantly organic pain (Almay et al., 1978). Admittedly, other studies find no relationship between opioid activity and psychiatric status (Naber et al., 198 1) and the diversity of assay techniques cited makes it possible that completely different biological variables are being assessed. Nevertheless pendorphin may reflect pain, stress, or mood disturbance as a state or trait marker. Since depressive disorders are frequently associated with chronic pain, further exploration of their biological relationship might have important therapeutic implications. We therefore have begun a series of studies to (I) assess p-endorphinl P-lipotropinlike immunoreactivity in normal subjects, psychiatric patients, and chronic pain patients with and without major psychiatric components to their pain syndrome; and (2) to examine possible correlations between fi-endorphinl P-lipotropin-like immunoreactivity and intensity of mood disturbance. We determined plasma fi-endorphin/ P-lipotropin-like immunoreactivity in chronic pain patients in whom the physical findings insufficiently explained the degree of invalidism, and in whom psychological factors were thought to help perpetuate the pain-disability syndrome. We hypothesized that pain patients would have elevated concentrations of P-endorphin//%lipotropin-like immunoreactivity and used comparison groups of psychiatric patients and normal volunteers. Concurrently, we investigated dexamethasone resistance, mood, and family histories of affective disorder and alcoholism
as objective
evidence
of mood
disturbance.
Methods Subjects. Seven chronic pain patients (six male, one female) were veterans being treated in medical-surgical out-patient clinics and were admitted to the University of California-San Diego Veterans Administration Hospital (UCSD-SDVAH) inpatient pain service because appropriate medical therapy had failed to alleviate pain or reverse progressive invalidism. Chronic pain was defined as pain on a daily basis for at least 6 months. Seven normal male volunteers and seven male veterans requiring hospitalization for psychiatric illness at the same institution served as comparison groups. Normal volunteers were free from medical illness and psychiatric history. Pain patients had the following physical disorders contributing to their pain. Four patients had osteoarthritis: three (# I, #3, #7) had cervical osteoarthritis with or without spondylosis and one (#6) had lumbar disease with radiculopathy. One patient (#4) had chronic pain resulting from multiple traumatic fractures (1974); one (#2) had left-sided pain in the context of remote pancreatitis; and one (#5) had chronic pain following thoracotomy (1975). All pain patients were opiate-free 3 weeks before admission. Three pain patients (#I, #2, #6) were being treated with antidepressants (protriptyline, doxepin, and maprotiline, respectively), three patients (#3, #4, #7) were taking flurazepam or diazepam as a nighttime hypnotic; and four patients (#3, #4, #5, #6) were taking a nonsteroidal anti-inflammatory drug for analgesia (baclofen, indomethacin, napronen, and acetaminophen, respectively). Psychiatric patients were studied before drug treatment for their psychiatric disorder and had been off psychotropic medicaton for at least 2 weeks before evaluation. No patient had a medical illness associated with cortisol escape from dexamethasone, and no medications enhancing dexamethasone metabolism were being
321 administered. Analysis of variance indicated significant differences in ages between the study groups: mean age for normals 23.6 years (SD 1.53); for psychiatric patients 34.4 years (SD 13.0); and for pain patients 47.3 years (SD 8.2) (H q 12.26;df = 2;p < 0.05). Pairwise comparisons by two-tailed C/tests were reliably different for normals vs. psychiatric patients (U= 8; df= 7.7;~ < 0.05). for normals vs. pain patients (U = 0; @ q 7, 7; p < 0.01) and for pain vs. psychiatric patients (U = 9; df= 7. 7; p < 0.05). Procedure. Psychiatric diagnoses on all subjects were made before the study began by an experienced diagnostician using the Research Diagnostic Criteria (RDC) of Spitzer et al. (1977) (see Table I). In pain patients a diagnosis of situational major depression indicated that pain was the major antecedent to the affective episode. Independent of the RDC diagnostician. the pain unit neurosurgeon and psychiatrist (CDM) made a consensus diagnosis of a mixed pain syndrome in all pain patients, indicating that (I) both physical and emotional factors contributed to the individual’s pain or invalidism and (2) pain disability exceeded that expected from physical findings alone. The medical diagnosis was made before the study began by evidence of positive physical findings, the patient’s history and description of pain, and confirmatory electromyographic or radiographic data. An interview-administered questionnaire using the RDC of Endicott and others (Spitzer et al., 1977; Endicott et al., 1978) was given to all subjects to determine personal histories of affective disorder and alcoholism as well as family history of affective illness, alcoholism, and pain in first-degree relatives. In addition, on the first day of blood sampling for endocrine studies, the Beck Depression Inventory (BDI) (Beck and Beamesderfer, 1974) and Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1960) were administered by an investigator who was unaware of the patient’s diagnosis.
Plasma samples were obtained as follows for baseline and postdexamethasone serum cortisol determination and for a predexamethasone 0800h determination of a-endorphin/Plipotropin-like immunoreactivity concentrations. At 0730h on day I an l&gauge heparin-lock catheter was inserted in a forearm vein for subsequent plasma sampling at 0800h, 1600h, and 2300h. Dexamethasone (I mg) was administered orally at 2300h on day I. Patients fasted from 2300h on day I until 0800h on day 2, and blood samples were drawn at 0800h, 1600h, and 2300h on day 2 for serum cortisol determination. Serum cortisol was measured by the method of Murphy et al. (1963); nonsuppression was defined as any serum cortisol concentration greater than 5 pg/dl at any of the three sampling times after dexamethasone. Blood for p-endorphinj plipotropin-like immunoreactivity was collected into Lhilled EDTA-containing vacutainers. The samples were placed immediately in ice and centrifuged at 3500 rpm at -4’C for IO minutes, then aliquoted into polypropylene vials, and stored at -80°C until assayed. Plasma p-endorphin//3lipotropin-like immunoreactivity concentrations were measured by the radioimmunoassay method of Guillemin et al. (1977~). The antibody for P-endorphin is 100% cross-reactive with P-lipotropin and with pro-opiomelanocortin. The sensitivity of the assay is approximately 20 pg/ ml, the IC,, is 3 I2 pg, the range is 20-5000 pg, and the within-assay variability is usually t IO Pg. Tests.
Statistical Analysis. The frequency of dexamethasone resistance was assessed by the Fisher exact probability test. Plasma /3-endorphin data were treated using analysis of variance (ANOVA) and Mann-Whitney tests for independent samples. Intercorrelations among /3endorphin concentrations and clinical depression scores were calculated using Spearman rank correlation coefficients for variable pairs.
Results Table 1 summarizes the neuroendocrine and clinical findings in this study. An ANOVA of mean levels (* SD) of 0800h predexamethasone plasma P-endorphin/Plipotropin-like immunoreactivity indicated significant group differences (H= 16.89; df
322
+
1
+
+
m
, /
I I
, , i I
I
+
+
+
+
323
324 = 7, 7; p < 0.01). Pairwise comparisons revealed that the mean &endorphin/Plipotropin-like immunoreactivity concentration in pain patients (n 7, mean = 97.4 pg/ml, SD 35.6) was reliably higher than in psychiatric patients (n 7, mean = 48.9 pg/ml, SD = 4.6) and normal volunteers (n = 7, mean 36.5 pg/ ml, SD = 11.1) (pain vs. affectivedisorder U=O; df=7,7;p
q
q
q
q
q
Discussion The major findings of this study were that chronic pain patients: (1) demonstrated elevated concentrations of /3-endorphinl P-lipotropin-like immunoreactivity, and (2) showed resistance to dexamethasone suppression of the limbic-hypothalamicpituitary-adrenal (LHPA) axis. This latter result confirms the finding of Blumer et al. (1982) of an abnormal DST in 30-40s of chronic pain patients. It was not possible to account for differences in plasma /3-endorphinl P-lipotropin-like immunoreactivity concentrations between pain patients and psychiatric subjects by differences in affective distress alone. Other variables, such as pain itself, may be involved, These results should be interpreted conservatively in view of several methodological considerations. First, four pain patients were taking nonsteroidal anti-inflamatory analgesics. It is unknown whether some of the agents affect LHPA axis activity (e.g., baclofen and napronen). Indomethacin apparently does not alter dexamethasone challenge of the LHPA axis in normals (Beirne and Jubiz, 1978) but in affectively ill subjects may produce a false-negative DST and convert nonsuppressors into suppressors (Mathe et al., 1982). In this regard it is of interest that patient #4 was a DST nonsuppressor despite the apparent use of indomethacin. Salicylates, although not used by these patients, have been variously reported to augment the secretion of adrenocorticotropin and cortisol under conditions of stress (Beirne and Jubiz, 1978) and to blunt the adrenocorticotropin but leave the cortisol response unchanged under challenge by insulin-induced hypoglycemia (Cavagnini et al., 1979). Another issue, apparent from the low Hamilton rating scores, is that several
325 psychiatric patients were not in full-blown affective episodes at the time of study. This limits the inferences which might be made about these findings as reflecting potential relationships between pain and depression. Even so, it is interesting that pendorphin/ /I-lipotropin-like immunoreactivity was elevated and significantly correlated with observer-rated level of depression in psychiatric patients, especially since patients with affective illness have been noted to have relative analgesia to painful stimuli (Davis et al., 1979). It should also be noted that our P-endorphin/&lipotropin-like immunoreactivity concentrations are considerably higher than those reported by some laboratories, probably refecting assay differences and degree of cross-reactivity. There is evidence at the clinical level that pain and depression are intimately related. It is generally acknowledged that chronic pain patients suffer a depressive mood disturbance at some point in their pain careers (Sternbach, 1974) with estimates of prevalence of depression ranging from 10% (Pilowsky et al., 1977) to 90% (Lindsay and Wyckoff, 198 1). The common presence of depressive symptoms among chronic pain patients may be secondary to prolonged physical suffering (Sternbach, 1974). Alternatively, some chronic pain patients who have no demonstrable organic evidence of disease are postulated to suffer a masked depression (Lopez-Ibor, 1965). In this regard Blumer et al. (1982) interpreted the finding of an abnormal DST in 40% of a sample of patients with chronic psychogenic pain as evidence that this condition was a variant of primary affective disorder. It is possible that resistance to dexamethasone and elevated P-endorphinl &lipotropin-like immunoreactivity concentrations represent markers of affective disorder in the present study of chronic pain patients. If so, the use of both markers and the evaluation of suppression of /3-endorphin/P-lipotropinlike immunoreactivity by dexamethasone might provide for more accurate detection and classification of mood disorders (Matthews et al., 1982). The complex interplay of physical and psychological disorders in chronic pain may require alternative explanations for these findings. Circulating plasma concentrations of P-endorphin-like material may reflect the level of central nervous system (CNS) arousal (Dubois et al., 1981). In this model high concentrations of opioid peptides detected during periods of acute stress indicate an easily activated or stress-responsive system, while low levels imply the converse. Since adrenocorticotropic hormone and /I-endorphin/P-lipotropin are co-released by the anterior pituitary during stress and pain (Guillemin et al., 19776), elevated opioid immunoreactivity and failure to suppress cortisol may reflect arousal in a pain-responsive CNS, and may not be related to affective disorder. It would be unwise to extend the findings from acute phenomena to more chronic conditions, and as yet it is also not clear that chronic pain is a stressor capable of producing sustained elevations of opioid-like material. Longitudinal studies to compare differing levels of severity of pain and degree of mood disturbance in diagnostically homogeneous groups are needed. These studies should be coupled with simultaneous measurement of ACTH, /3-endorphin, and cortisol during challenges which activate and suppress endogenous opioid systems. Acknowledgment.
NOI-CN-85417-06.
This research was supported in part by National Cancer Institute Contract The authors thank Pattie L. Krohn for expert technical assistance.
326 References
Almay, B.G.L., Johansson, F., von Knorring, L., Terenius, L., and Wahlstrom, A. Endorphins in chronic pain: I. Differences in CSF endorphin levels between organic and psychogenic pain syndrome. Pain, 5, 153 (1978). Beck, A.T., and Beamesderfer, A. Assessment of depression: The Depression Inventory. In: Pichot, P., ed. Modern Problems in Pharmacopsychiatry. S. Karger A.G., Base1 (1974). Beirne, J., and Jubiz, W. Effect of indomethacin on the hypothalamic-pituitary-adrenal axis in man. Journal of Clinical Endocrinology and Metabolism, 41, 7 13 (1978). Blumer, D., Zorick, F., Heilbronn, M., and Roth, T. Biological markers for depression in chronic pain. Journal of Nervous and Mental Disease, 170,425 (1982). Cavagnini, F., DiLandro, A., Maraschini, C., Invitti, C., and Pinto, M.L. Effect of two prostaglandin synthesis inhibitors, indomethacin and acetylsalicylic acid, on plasma ACTH and cortisol levels in man. Acta Endocrinologica, 91,666 (1979). Cohen, M.R., Pickar, D., Dubois, M., Roth, Y., Naber, D., and Bunney, W.E., Jr. Surgical stress and endorphins. Lancer, I, 213 (1981). Davis, G.C., Buchsbaum, M.S., and Bunney, W.E., Jr. Analgesia to painful stimuli in affective illness. American Journnl of Psychiatry, 136, 1148 (1979). Dubois, M., Pickar, D., Cohen, M., Roth, Y., McNamara, T., and Bunney, W.E., Jr. Surgical stress in humans is accompanied by an increase in a-endorphin immunoreactivity. Life Sciences,
29, 1249 (1981).
Endicott, J., Andreasen, N., and Spitzer, R.L. Family History Research Diagnostic Criteria. 3rd ed. New York State Psychiatric Institute, New York (1978). Gilkes, J.J.H., Bloomfield, G.A., Scott, A.P., Lowry, P.J., Ratcliffe, J.G., Landon, J., and Rees, L.H. Development and validation of a radioimmunoassay for peptides related to P-melanocyte-stimulating hormone in human plasma: Lipotropins. Journal of Clinical Endocrinology
Guillemin,
and Metabolism,
40, 450 (1975).
R., Ling, N., and Vargo, T. Radioimmunoassay
Biochemical
and Biophysical
Research
Communications,
for a-endorphin 17,361
and /?-endorphin.
(1977a).
Guillemin, R., Vargo, T., Rossier, J., Minick, S., Ling, N., Rivier, C., Vale, W., and Bloom, F. Beta-endorphin and adrenocorticotropin are secreted concomitantly by the pituitary gland. Science, 197, 1376 (19776). Hamilton, M. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56 (1960).
Lindsay, P.G., and Wyckoff, M. The depression-pain syndrome and its response to antidepressants. Psychosomatics, 22, 571 (1981). Lopez-Ibor, J.J. Masked depressions. British Journal of Psychiatry, 120,245 (1965). Math& A.A., Davis, B.M., Levy, M.I., Horvath, T.B., and Davis, K.L. Indomethacin reverses dexamethasone suppression. Presented at the 135th Annual Meeting of the American Psychiatric Association, Toronto, Canada, May 15-20 (1982). Matthews, J., Akil, H., Greden, J., and Watson, S. Plasma measures of a-endorphin-like immunoreactivity in depressives and other psychiatric subjects. Life Sciences, 31, 1867 (1982). Morley, J., and Levine, A. Stress induced eating is mediated through endogenous opiates. Science,
209, 1259 ( 1980).
Murphy, B.P., Engelbert, W., and Pattee, C.J. Simple method for the determination of plasma corticoids. Journal of Clinical Endocrinology and Metabolism, 23, 293 (1963). Naber, D., Pickar, D., Post, R.M., Van Kammen, D.P., Waters, R.N., Ballenger, J.C., Goodwin, F.K., and Bunney, W.E. Endogenous opioid activity and P-endorphin immunoreactivity in CSF of psychiatric patients and normal volunteers. American Journal of Psychiatry,
138, 1457 (1981).
Pilowsky, I., Chapman, C.R., and Bonica, J.J. Pain, depressions, clinic population. Pain, 4, 183 (1977).
and illness behavior
in a pain
327 Risch, SC. Plasma P-endorphin hypersecretion in depression: Possible cholinergic mechanisms. Biological Psychiatry, 17, 107 1 (1982). Spitzer, R.L., Endicott, J., and Robins, E. Research Diagnostic Criteria (RDC)for a Selected Group of Functional Disorders. 3rd ed. New York State Psychiatric Institute, New York (1977). Sternbach, R.A. Pain Patients: Traits and Treatment. Academic Press, New York (1974). Terenius, L., Wahlstrom, A., and Agren, H. Naloxone (Narcan) treatment in depression: Clinical observations and effects on CSF endorphins and monoamine metabolites. Psychopharmacology, 154, 3 1 (1977).
319
Elsevier
of Plasma Measures Like lmmunoreactivity Psychiatric Subjects
Beta-Endorphin/Beta-Lipotropinin Chronic Pain Syndrome
and
Joseph H. Atkinson, Edwin F. Kremer, Samuel C. Risch, Charles Morgan, Raana Fryer Azad, Cindy L. Ehlers, and Floyd E. Bloom Received
March
10, 1983: revised
version
received
July 15, 1983; accepted
D.
July 25, 1983.
Abstract. This study compared basal concentrations of plasma B-endorphin/Plipotropin-like immunoreactivity and dexamethasone suppression of cortisol in seven chronic pain patients, seven psychiatric disorder patients, and seven normal volunteers. Pain patients and psychiatric patients showed significantly higher basal concentrations of /3-endorphin/a-lipotropin-like immunoreactivity compared to normal volunteers. Pain patients also had significantly higher P-endorphin//S lipotropin-like immunoreactivity than psychiatric patients, even though there was no significant difference in severity of depressive symptomatology as assessed by Beck and Hamilton scores. Resistance to dexamethasone occurred in 57% of pain patients. These results may indicate that biological markers for depression occur in populations of chronic pain patients, or may reflect levels of central nervous system arousal in response to stress, pain, or nonaffective phenomena. Key Words. /3-Endorphin//_Uipotropin-like suppression test, chronic pain, depression.
immunoreactivity,
dexamethasone
P-Endorphin is thought to be involved in the mediation of pain perception. Several groups also have shown that P-endorphin is increased acutely by stress in animals (Guillemin et al., 1977a) and man (Morley and Levine, 1980; Cohen et al., 1981; Dubois et al., 1981), as is adrenocorticotropin (ACTH) (Guillemin et al., 1977b) and fi-lipotropin (b-LPH) (Gilkes et al., 1975). Therefore, an elevated concentration of /3-endorphin may reflect the body’s response to acute pain or stress. Other preliminary evidence indicates, however, that P-endorphin may be related to psychiatric symptomatology. Risch (1982) noted that morning plasma concentrations of P-endorphin/Plipotropin-like immunoreactivity detected by radioimmunoassay were significantly higher in a group of depressed patients meeting Research Diagnostic Criteria (RDC) (Spitzer et al., 1977) for major depressive disorder or schizoaffective disorder, depressed, than in groups of normal volunteers and psychiatric patients without affective disorders. A radioreceptor assay plus fractionation used by Terenius et al.
Joseph H. Atkinson, Jr., M.D., Edwin F. Kremer, Ph.D., Samuel C. Risch, M.D., Charles D. Morgan, M.D., and Cindy L. Ehlers. Ph.D.,are in the Department of Psychiatry(M-O03), University of Californiaat San Diego School of Medicine, La Jolla, CA 92093, USA. Raana Fryer Azad, M.S., and Floyd E. Bloom, M.D.. are at the Salk Institute of Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. (Reprint requests to Dr. J.H. Atkinson, Jr.) 01651781:83~$03.00
@ 1983 Elsevier Science Publishers
B.V.
320 (1977) to assess opioid peptides intermediate in size between met-enkephalin and /I-endorphin detected elevated fraction I endorphins in depressed patients. This group also noted that concentrations of fraction I endorphins isolated from cerebrospinal fluid (CSF) were jiositively correlated with depressive symptomatology in chronic pain patients, and were significantly higher in patients with predominantly psychogenic chronic pain than in those with predominantly organic pain (Almay et al., 1978). Admittedly, other studies find no relationship between opioid activity and psychiatric status (Naber et al., 198 1) and the diversity of assay techniques cited makes it possible that completely different biological variables are being assessed. Nevertheless pendorphin may reflect pain, stress, or mood disturbance as a state or trait marker. Since depressive disorders are frequently associated with chronic pain, further exploration of their biological relationship might have important therapeutic implications. We therefore have begun a series of studies to (I) assess p-endorphinl P-lipotropinlike immunoreactivity in normal subjects, psychiatric patients, and chronic pain patients with and without major psychiatric components to their pain syndrome; and (2) to examine possible correlations between fi-endorphinl P-lipotropin-like immunoreactivity and intensity of mood disturbance. We determined plasma fi-endorphin/ P-lipotropin-like immunoreactivity in chronic pain patients in whom the physical findings insufficiently explained the degree of invalidism, and in whom psychological factors were thought to help perpetuate the pain-disability syndrome. We hypothesized that pain patients would have elevated concentrations of P-endorphin//%lipotropin-like immunoreactivity and used comparison groups of psychiatric patients and normal volunteers. Concurrently, we investigated dexamethasone resistance, mood, and family histories of affective disorder and alcoholism
as objective
evidence
of mood
disturbance.
Methods Subjects. Seven chronic pain patients (six male, one female) were veterans being treated in medical-surgical out-patient clinics and were admitted to the University of California-San Diego Veterans Administration Hospital (UCSD-SDVAH) inpatient pain service because appropriate medical therapy had failed to alleviate pain or reverse progressive invalidism. Chronic pain was defined as pain on a daily basis for at least 6 months. Seven normal male volunteers and seven male veterans requiring hospitalization for psychiatric illness at the same institution served as comparison groups. Normal volunteers were free from medical illness and psychiatric history. Pain patients had the following physical disorders contributing to their pain. Four patients had osteoarthritis: three (# I, #3, #7) had cervical osteoarthritis with or without spondylosis and one (#6) had lumbar disease with radiculopathy. One patient (#4) had chronic pain resulting from multiple traumatic fractures (1974); one (#2) had left-sided pain in the context of remote pancreatitis; and one (#5) had chronic pain following thoracotomy (1975). All pain patients were opiate-free 3 weeks before admission. Three pain patients (#I, #2, #6) were being treated with antidepressants (protriptyline, doxepin, and maprotiline, respectively), three patients (#3, #4, #7) were taking flurazepam or diazepam as a nighttime hypnotic; and four patients (#3, #4, #5, #6) were taking a nonsteroidal anti-inflammatory drug for analgesia (baclofen, indomethacin, napronen, and acetaminophen, respectively). Psychiatric patients were studied before drug treatment for their psychiatric disorder and had been off psychotropic medicaton for at least 2 weeks before evaluation. No patient had a medical illness associated with cortisol escape from dexamethasone, and no medications enhancing dexamethasone metabolism were being
321 administered. Analysis of variance indicated significant differences in ages between the study groups: mean age for normals 23.6 years (SD 1.53); for psychiatric patients 34.4 years (SD 13.0); and for pain patients 47.3 years (SD 8.2) (H q 12.26;df = 2;p < 0.05). Pairwise comparisons by two-tailed C/tests were reliably different for normals vs. psychiatric patients (U= 8; df= 7.7;~ < 0.05). for normals vs. pain patients (U = 0; @ q 7, 7; p < 0.01) and for pain vs. psychiatric patients (U = 9; df= 7. 7; p < 0.05). Procedure. Psychiatric diagnoses on all subjects were made before the study began by an experienced diagnostician using the Research Diagnostic Criteria (RDC) of Spitzer et al. (1977) (see Table I). In pain patients a diagnosis of situational major depression indicated that pain was the major antecedent to the affective episode. Independent of the RDC diagnostician. the pain unit neurosurgeon and psychiatrist (CDM) made a consensus diagnosis of a mixed pain syndrome in all pain patients, indicating that (I) both physical and emotional factors contributed to the individual’s pain or invalidism and (2) pain disability exceeded that expected from physical findings alone. The medical diagnosis was made before the study began by evidence of positive physical findings, the patient’s history and description of pain, and confirmatory electromyographic or radiographic data. An interview-administered questionnaire using the RDC of Endicott and others (Spitzer et al., 1977; Endicott et al., 1978) was given to all subjects to determine personal histories of affective disorder and alcoholism as well as family history of affective illness, alcoholism, and pain in first-degree relatives. In addition, on the first day of blood sampling for endocrine studies, the Beck Depression Inventory (BDI) (Beck and Beamesderfer, 1974) and Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1960) were administered by an investigator who was unaware of the patient’s diagnosis.
Plasma samples were obtained as follows for baseline and postdexamethasone serum cortisol determination and for a predexamethasone 0800h determination of a-endorphin/Plipotropin-like immunoreactivity concentrations. At 0730h on day I an l&gauge heparin-lock catheter was inserted in a forearm vein for subsequent plasma sampling at 0800h, 1600h, and 2300h. Dexamethasone (I mg) was administered orally at 2300h on day I. Patients fasted from 2300h on day I until 0800h on day 2, and blood samples were drawn at 0800h, 1600h, and 2300h on day 2 for serum cortisol determination. Serum cortisol was measured by the method of Murphy et al. (1963); nonsuppression was defined as any serum cortisol concentration greater than 5 pg/dl at any of the three sampling times after dexamethasone. Blood for p-endorphinj plipotropin-like immunoreactivity was collected into Lhilled EDTA-containing vacutainers. The samples were placed immediately in ice and centrifuged at 3500 rpm at -4’C for IO minutes, then aliquoted into polypropylene vials, and stored at -80°C until assayed. Plasma p-endorphin//3lipotropin-like immunoreactivity concentrations were measured by the radioimmunoassay method of Guillemin et al. (1977~). The antibody for P-endorphin is 100% cross-reactive with P-lipotropin and with pro-opiomelanocortin. The sensitivity of the assay is approximately 20 pg/ ml, the IC,, is 3 I2 pg, the range is 20-5000 pg, and the within-assay variability is usually t IO Pg. Tests.
Statistical Analysis. The frequency of dexamethasone resistance was assessed by the Fisher exact probability test. Plasma /3-endorphin data were treated using analysis of variance (ANOVA) and Mann-Whitney tests for independent samples. Intercorrelations among /3endorphin concentrations and clinical depression scores were calculated using Spearman rank correlation coefficients for variable pairs.
Results Table 1 summarizes the neuroendocrine and clinical findings in this study. An ANOVA of mean levels (* SD) of 0800h predexamethasone plasma P-endorphin/Plipotropin-like immunoreactivity indicated significant group differences (H= 16.89; df
322
+
1
+
+
m
, /
I I
, , i I
I
+
+
+
+
323
324 = 7, 7; p < 0.01). Pairwise comparisons revealed that the mean &endorphin/Plipotropin-like immunoreactivity concentration in pain patients (n 7, mean = 97.4 pg/ml, SD 35.6) was reliably higher than in psychiatric patients (n 7, mean = 48.9 pg/ml, SD = 4.6) and normal volunteers (n = 7, mean 36.5 pg/ ml, SD = 11.1) (pain vs. affectivedisorder U=O; df=7,7;p
q
q
q
q
q
Discussion The major findings of this study were that chronic pain patients: (1) demonstrated elevated concentrations of /3-endorphinl P-lipotropin-like immunoreactivity, and (2) showed resistance to dexamethasone suppression of the limbic-hypothalamicpituitary-adrenal (LHPA) axis. This latter result confirms the finding of Blumer et al. (1982) of an abnormal DST in 30-40s of chronic pain patients. It was not possible to account for differences in plasma /3-endorphinl P-lipotropin-like immunoreactivity concentrations between pain patients and psychiatric subjects by differences in affective distress alone. Other variables, such as pain itself, may be involved, These results should be interpreted conservatively in view of several methodological considerations. First, four pain patients were taking nonsteroidal anti-inflamatory analgesics. It is unknown whether some of the agents affect LHPA axis activity (e.g., baclofen and napronen). Indomethacin apparently does not alter dexamethasone challenge of the LHPA axis in normals (Beirne and Jubiz, 1978) but in affectively ill subjects may produce a false-negative DST and convert nonsuppressors into suppressors (Mathe et al., 1982). In this regard it is of interest that patient #4 was a DST nonsuppressor despite the apparent use of indomethacin. Salicylates, although not used by these patients, have been variously reported to augment the secretion of adrenocorticotropin and cortisol under conditions of stress (Beirne and Jubiz, 1978) and to blunt the adrenocorticotropin but leave the cortisol response unchanged under challenge by insulin-induced hypoglycemia (Cavagnini et al., 1979). Another issue, apparent from the low Hamilton rating scores, is that several
325 psychiatric patients were not in full-blown affective episodes at the time of study. This limits the inferences which might be made about these findings as reflecting potential relationships between pain and depression. Even so, it is interesting that pendorphin/ /I-lipotropin-like immunoreactivity was elevated and significantly correlated with observer-rated level of depression in psychiatric patients, especially since patients with affective illness have been noted to have relative analgesia to painful stimuli (Davis et al., 1979). It should also be noted that our P-endorphin/&lipotropin-like immunoreactivity concentrations are considerably higher than those reported by some laboratories, probably refecting assay differences and degree of cross-reactivity. There is evidence at the clinical level that pain and depression are intimately related. It is generally acknowledged that chronic pain patients suffer a depressive mood disturbance at some point in their pain careers (Sternbach, 1974) with estimates of prevalence of depression ranging from 10% (Pilowsky et al., 1977) to 90% (Lindsay and Wyckoff, 198 1). The common presence of depressive symptoms among chronic pain patients may be secondary to prolonged physical suffering (Sternbach, 1974). Alternatively, some chronic pain patients who have no demonstrable organic evidence of disease are postulated to suffer a masked depression (Lopez-Ibor, 1965). In this regard Blumer et al. (1982) interpreted the finding of an abnormal DST in 40% of a sample of patients with chronic psychogenic pain as evidence that this condition was a variant of primary affective disorder. It is possible that resistance to dexamethasone and elevated P-endorphinl &lipotropin-like immunoreactivity concentrations represent markers of affective disorder in the present study of chronic pain patients. If so, the use of both markers and the evaluation of suppression of /3-endorphin/P-lipotropinlike immunoreactivity by dexamethasone might provide for more accurate detection and classification of mood disorders (Matthews et al., 1982). The complex interplay of physical and psychological disorders in chronic pain may require alternative explanations for these findings. Circulating plasma concentrations of P-endorphin-like material may reflect the level of central nervous system (CNS) arousal (Dubois et al., 1981). In this model high concentrations of opioid peptides detected during periods of acute stress indicate an easily activated or stress-responsive system, while low levels imply the converse. Since adrenocorticotropic hormone and /I-endorphin/P-lipotropin are co-released by the anterior pituitary during stress and pain (Guillemin et al., 19776), elevated opioid immunoreactivity and failure to suppress cortisol may reflect arousal in a pain-responsive CNS, and may not be related to affective disorder. It would be unwise to extend the findings from acute phenomena to more chronic conditions, and as yet it is also not clear that chronic pain is a stressor capable of producing sustained elevations of opioid-like material. Longitudinal studies to compare differing levels of severity of pain and degree of mood disturbance in diagnostically homogeneous groups are needed. These studies should be coupled with simultaneous measurement of ACTH, /3-endorphin, and cortisol during challenges which activate and suppress endogenous opioid systems. Acknowledgment.
NOI-CN-85417-06.
This research was supported in part by National Cancer Institute Contract The authors thank Pattie L. Krohn for expert technical assistance.
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