Anesth Prog 34:93-98 1990
Psychoneuroimmunology: Chronic Orofacial Pain
Potenil Relevnce to
Steven J. Schleifer, MD,* Joseph Marbach, DDS,t Steven E. Keller, PhD* *University of Medicine and Dentistry of New Jersey, Newark, New Jersey; tColumbia University, New York, New York
patients with chronic pain,2 however, these states are characterized by a number of factors that are likely to be associated with altered immunity. Patients suffering with chronic pain often expenence high levels of stress, demoralization, and depression; they tend to use a variety of prescribed and selfadministered drugs that may alter immune processes; and they may also suffer from other systemic disorders that can alter the immune system.3 Pain states may be associated with changes in endogenous opioids, which are believed to be involved in immunoregulation, in addition to eliciting the use of exogenous opioids. This presentation will review psychoimmunologic studies from our laboratory and others suggesting that stress, depression, and the pain syndrome itself may have psychoimmunologic consequences in patients with chronic facial pain.
Studies undertaken over the past ten years have demonstrated that stress and depression can induce immune alterations, including decreased numbers of immunocompetent cells and impaired lymphocyte and natural killer cell activity. Factors such as age and severity of symptomatology influence these effects. The substantial stress and depression associated with chronic pain syndromes and the evidence for opioid involvement in immunomodulation suggest that immune system changes may occur in some patients with chronic facial pain.
There is increasing evidence that behavioral and psychological factors can influence the immune system and that these effects may contribute to the onset and course of disease.' These factors include exposure to stress, psychological symptoms or syndromes such as depression, and the use of alcohol, opioids, and other drugs. Psychoimmunologic changes may be the direct result of central processes mediated by neural and neuroendocrine systems, or may be effected behaviorally as by exposure to immunoactive chemicals or by changes in activity, sleep, or nutrition that can alter the immune system. Psychoimmunologic effects may be exaggerated or mitigated in patients with concurrent medical disorders that have immunologic effects.
LIFE STRESS AND IMMUNITY
That psychosocial processes influence immunity was suggested by studies demonstrating that the brain is involved in the regulation of the immune system. Evidence, derived primarily from lesion studies, have implicated the midbrain, the anterior hypothalamus, and the cerebral hemispheres in both T and B cell activity. Animal studies demonstrated that a variety of stressors can alter humoral (B cell) and cell-mediated (T-cell) immune responses.' Effects on both T and B cell functions are associated with characteristics of the stressor such as chronicity4 and intensity.5 Other research demonstrated influences of higher cortical function on immune processes. Laudenslager and Ryan6 presented evidence that stress-induced suppression of lymphocyte function is related to the animal's having control over the stressor. Ader and others' found conditioning effects on both humoral and cell-mediated immunity. These animal studies demonstrate that
Litfle is known conceming immunologic processes in
Address correspondence to Steven J. Schleifer, MD, Associate Professor, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Departnent of Psychiatry, 185 South Orange Avenue, MSB, E501, Newark, NJ 07103-2757. C 1990 by the American Dental Society of Anesthesiology
ISSN 0003-3006/90/$3.50
93
94 Psychoneuroimmunology and Chronic Pain
specific central nervous system (CNS) behavioral processes can influence the immune system. Research on life stress and immunity in man has identified several conditions in which altered, primarily suppressed immunity occurs. The death of a spouse was among the first life experiences investigated in relation to the immune system, as it is one of the most stressful commonly occurring events. Bereavement has also been linked to medical mortality.78 Bartrop and coworkers9 first reported alterations in the immune system in the bereaved. They found lower mitogen-induced lymphocyte stimulation in bereaved spouses compared with matched controls, suggesting that the functional capacity of the lymphocyte was altered in the bereaved. We investigated bereavement and immunity in a prospective study of healthy spouses of women with advanced breast carcinoma. 11 In vitro measures of immunity were obtained at 6 to 8-week intervals. The mean levels of mitogen-induced lymphocyte stimulation before death of a spouse were compared with that obtained during the first two months postbereavement and then during the latter part of the postbereavement year. Responses to the mitogens phytohemagglutinin (PHA), concanavalin A (ConA), and pokeweed mitogen (PWM) were significantly lower during the first two months postbereavement compared with those obtained prebereavement. By the end of the postbereavement year, mitogen responses had returned to prebereavement levels for the majority but not all of the subjects. Although individual mitogen data must be interpreted with caution due to the considerable day to day variability of the assays,11 our study suggested that there are differing response patterns among the bereaved. While many showed a greater than 50% suppression of mitogen responses postbereavement, several spouses showed little or no change soon after bereavement. The latter, however, had decreased mitogen responsivity later in the postbereavement year-when the majority of subjects were showing a return to prebereavement levels. This delayed response group tended to be younger, suggesting that age may be an important cofactor in psychoimmunologic processes. Altered nutrition, activity and exercise levels, sleep, and drug use, often found in the widowed, must also be taken into account, although our subjects did not report major changes in these parameters. Another important component of the immune system, natural killer (NK) cell activity, also has been found to be altered in relation to bereavement and related stress states. Irwin and coworkers'2 studied NK function in women experiencing a spouse's metastatic cancer and bereavement. They found lower NK activity in women who had experienced major stressful life experiences compared with women who had few life changes. The effects of more minor life stressors have also been
Anesth Prog 34:93-98 1990
investigated-with most studies of students undergoing academic examinations. Several studies'3'57 found altered mitogen responses in psychiatric residents and medical students during examination periods. Kiecolt-Glaser et al.'4 found lower NK cell function in medical students taking final examinations. In contrast, other moderate stressful conditions have not been found to alter immune measures. Both our group'5 and Linn and Jensen'6 found that otherwise healthy patients hospitalized for elective surgery did not show changes in lymphocyte mitogen responses when compared with controls. NK cell activity, however, which may be more sensitive to minor stress states, was not investigated in these studies, and research including a range of immunologic parameters in various stress conditions is needed.
DEPRESSION AND IMMUNITY
Changes in affective state, including the development of clinically significant depression, could be involved in the effects of bereavement and other stressors on immunity. Bereavement is associated with persistent changes in mood state and in appetite functions, sleep, and activity levels that often suggest the presence of clinical affective disorder.7",8 Depression, like bereavement, has been associated with increased medical mortality,'9-2' as well as with immune-related disorders.19'22'23 Furthermore, neuroendocrine functions that may influence immunologic processes are altered in many depressed patients.2425 Several studies have suggested that effects of life stress on immunity are associated with depressive reactions. The studies of Kiecolt-Glaser et al.'4 and Irwin et al.'2 both suggest that life stress results in greater immune suppression when affective disturbances are present. These observations suggest that depression may be a major factor in psychoimmunologic processes. Studies of immunity in patients with clinical affective disorders support this notion. Several reports have noted the presence of autoimmune markers in patients with depression.26-28 Studies of lymphocyte activity in depressed patients were first reported by Cappel and coworkers23 who found altered mitogen responses during the acute phase of depressive illness. Similarly, Kronfol and coworkers29 found lower mitogen responses in depressed patients than in psychiatric and normal controls. We investigated immune processes in medication-free subjects with major depressive disorder studied on the same day with age- and sex-matched controls. We found that hospitalized patients with major depression had significantly decreased numbers of circulating lymphocytes (T and B cells) and decreased lymphocyte mitogen responses (PHA, ConA, and PWM) compared with con-
Anesth Prog 34:93-98 1990 trols.30 To determine the specificity of these effects, we studied ambulatory patients with major depression15 and found that they did not differ from controls. This suggested that altered lymphocyte activity in depressed inpatients was related either to the severity of depression or to hospitalization itself. Studies of otherwise healthy hospitalized patients with schizophrenia and of subjects hospitalized for elective surgery,15 however, found no differences in mitogen response from controls indicating that hospitalization, per se, is not a determining psychoimmunologic factor. Linn and Jensen16 similarly did not find mitogen changes in otherwise healthy patients hospitalized for elective surgery. To further investigate the contribution of severity of depression, hospitalization, age, and gender, we more recently investigated a sample of 91 hospitalized and ambulatory major depressive disorder patients.1" This study used an expanded battery of immune functions and included patients across a range of ages, illness severity, and sex. As in prior studies, diagnoses of major depressive disorder were made using strict diagnostic criteria31 and the Hamilton Depression Rating Scale (HDRS)32 was used as the index of severity. Patients were studied on the same day with healthy age- and sex-matched controls. The assays included lymphocyte stimulation by the mitogens PHA, ConA, and PWM; quantification of the number of peripheral blood lymphocytes and lymphocyte subsets; and NK cell activity. The pooled sample of depressed patients did not differ from the matched controls (ANOVA) on any of the immune measures, indicating that altered immunity is not invariably characteristic of all patients with depression. Significant differences between patients and controls were revealed, however, when age, sex, severity of depression, and hospitalization were considered using hierarchical multiple regression techniques [analysis of partial variance (APV)32]. We found that the relationship between age and lymphocyte function was significantly different in the controls and the patients for each of the mitogens; a similar pattern of differences was found for the number of T4 (Thelper) lymphocytes. It appears that, with increasing age in the middle and later years, patients with major depression have specific concurrent deficits in the numbers of T4 cells and in lymphocyte stimulation responses; the altered T-helper cells may contribute to the lymphocyte functional changes. In contrast to older depressed patients, depressed young adults may have relatively increased T4 cells and lymphocyte activity. In addition, a significant effect of severity of depression on lymphocyte function across all ages was found. The age-related immune changes in depressed patients, and possibly following bereavement, may represent an interaction between processes associated with depression and those associated with aging. Suppressed mitogen re-
Schleifer et al 95
activity in older and depressed patients may result from exaggerated neuroendocrine or autonomic nervous system changes in the older depressed patient33-35 imposed upon an immune system that has limited adaptive capacity due to immunosenescent processes. The age-related immune differences may also relate to differences in the depressive disorders found in younger and older patients. Our finding of a correlation between severity of depression and mitogen response, independent of age, suggest that at least some of the immunologic effects of depression are related to the state of depression. They are also consistent with an association between affective symptomatology and altered immunity, an effect that may be independent of syndromal status. Affective distress could therefore account for altered immunity both in depressive disorders and in stress-related states such as following bereavement.
MEDIATION OF IMMUNE CHANGES IN DEPRESSION AND FOLLOWING STRESS Depressive disorders are associated with changes in several neuroendocrine systems that can alter immune processes. Many of these systems are also altered in stress conditions and in pain states. Changes in the hypothalamic-pituitary-adrenal (HPA) axis following stress and in depression, some of which are age-related,33'36 have been demonstrated most consistently.25'36'37 Corticosteroids suppress lymphocyte proliferation38 and induce the redistribution of T-helper cells out of the peripheral blood.39 Abnormalities in the hypothalamic-pituitary-thyroid axis,"40 growth hormone,41 and sex steroids42 have also been demonstrated in depression, and each of these hormonal systems has been reported to modulate immune function.-45 Supporting the heterogeneity of neuroendocrine psychoimmunologic mechanisms are our findings in the rat, that there are both adrenal-dependent and adrenal-independent stress effects on the immune system.46 Alterations in immunity found in depression and other states may therefore involve diverse neuroendocrine processes. Influences other than those associated with classical neuroendocrine pathways may alter immunity in depression and following stress. Autonomic systems may be involved in modulation of immunity,47", and direct neural innervation of lymphoid tissue has been demonstrated.58 Dysregulated noradrenergic function in depression,35'49-51 which may be age-related' as may peripheral catecholamine output following stress, may contribute to altered immunity. We have found pituitary-independent changes in immunity in stressed hypophysectomized rats,52 providing additional evidence for multiple mechanisms in stressinduced immunomodulation. There is increasing interest in the potential role of pep-
Anesth Prog 34:93-98 1990
96 Psychoneuroimmunology and Chronic Pain
tides, especially the opioids, in the modulation of immunity. Endorphins are secreted together with ACTH in stress conditions and may play an important role in stress responses. Effects of endogenous opioids on immune processes have occasioned much interest; however, the research findings have been complex and at times inconsistent. Altered NK activity following exposure to opioid peptides may be age related and mediated via opioid receptors.59 In contrast, opioid effects on mitogen stimulation have been less consistently demonstrated and appear to be nonspecific. Shavit et al' have provided provocative evidence that opioids may be important modulators of immune changes following stressful conditions that are also "depressogenic." They found that, in rats, a stress paradigm inducing opioid-mediated analgesia and associated with leamed helplessness (an animal model of depression) resulted in suppressed NK function, whereas a stress paradigm mediated by nonopioid mechanisms was not NK suppressive. The opioids, as well as other peptides such as substance P,59 are of particular relevance to the study of immunity in patients with chronic pain as well as depression.
CHRONIC FACIAL PAIN, STRESS, DEPRESSION, AND IMMUNITY Chronic facial pain may provide an important model for the investigation of psychoimmunologic processes. Syndromes such as temporomandibular pain dysfunction syndrome (TMPDS) are associated with substantial functional morbidity, themselves act as stressors, and are marked by a state of pain that is not linked to systemic, hence potentially immunosuppressive, disease. The point of departure for the present research derived from striking findings in two of our prior studies on TMPDS patients. In the first study of 151 women with TMPDS and 139 healthy controls,3 TMPDS patients showed much higher levels of nonspecific distress, or demoralization. Demoralization is measured by 8 highly correlated symptom scales that include anxiety, sadness, poor self esteem, hopelessness-helplessness, dread, confused thinking, psychophysiological symptoms, and perceived physical health.53 The average score on the demoralization scale for the women with TMPDS (1.8 + 0.7) represented a score midway between the levels shown by the controls (1.1 + 0.5) and a comparable sample from another study of women psychiatric patients (mean = 2.5 + 0.7) who had had a recent episode of major depression.54 This suggested that some of the TMPDS women might meet criteria for a diagnosis of depression, indicating a comorbidity of TMPDS and depression. To investigate this possibility, a pilot study was conducted on a subsample of 20 of the TMPDS patients.55 DSM III-R diagnoses of current and lifetime depression
and other psychiatric disorders were obtained using a standardized semistructured diagnostic interview.56 Current (24%) and lifetime (69%) prevalence rates of depression among TMPDS cases (adjusted for sampling procedures) were much higher than those found in general population studies.61,62 These results suggest comorbidity of TMPDS and depression, with further descriptive and psychophysiological studies indicated. Chronic facial pain patients may therefore be at risk for alterations in immunity and possible secondary systemic morbidities. We recently initiated a study of immune function in women with TMPDS. The study was undertaken to investigate the psychoimmunologic effects of life stress and depressive reactions in patients with chronic facial pain, particularly in relation to potential interactions among the dimensions of pain, stress, and depression. Only patients otherwise in good health and not currently taking medications with demonstrated effects on the immune system have been included. This procedure tends to exclude the more severe TMPDS cases. Assessments of life stress, demoralization, and major depressive disorder have been conducted on 19 TMPDS patients and 19 age-sex matched controls. Blood for immunologic assessments was obtained from patients and their matched controls on the same day during the morning hours. Immunologic assays included quantitation of lymphocyte phenotypes and subtypes, mitogen-induced lymphocyte stimulation, and NK cell numbers and function. Preliminary analysis suggest that there are associations between demoralization and both mitogen-induced lymphocyte stimulation and NK activity. They suggest that changes in the immune system are found in some patients with chronic pain syndromes. The nature and extent of these effects require systematic investigation. REFERENCES 1. Ader R: Psychoneuroimmunology. New York, Academic Press, 1981. 2. Magni G: On the relationship between chronic pain and depression when there is no organic lesion. Pain 1987;31: 1-21. 3. Marbach JJ, Lennon MC, Dohrenwend BP: Candidate risk factors for temporomandibular pain and dysfunction syndrome: psychosocial, health behavior, physical illness and injury. Pain 1988;34:139-151. 4. Monjan AA, Collector MI: Stress-induced modulation of the immune response. Science 1977;196:307. 5. Keller SE, Weiss JM, Schleifer SJ, Miller E, Stein M: Suppression of immunity by stress: effect of a graded series of stressors on lymphocyte stimulation in the rat. Science 1981;213: 1397-1400. 6. Laudenslager ML, Ryan SM: Coping and immunosuppression: inescapable but not escapable shock suppresses lymphocyte proliferation. Science 1983;221:568. 7. Parkes CM, Benjamine B, Fitzgerald RG: Broken heart:
Anesth Prog 34:93-98 1990 a statistical study of increased mortality among widowers. Br Med J 1969;1:740-743. 8. Helsing KJ, Szklo M, Comstock GW: Factors associated with mortality after widowhood. Am J Public Health
1981;71:802. 9. Bartrop RW, Lazarus L, Luckherst E, Kiloh LH: Depressed lymphocyte function after bereavement. Lancet 1977;1:834. 10. Schleifer SJ, Keller SE, Camerino M, Thornton JC, Stein M: Suppression of lymphocyte stimulation following bereavement. JAMA 1983;250:374-377. 11. Schleifer SJ, Keller SE, Bond R, Cohen J, Stein M: Depression and immunity: Role of age, sex, and severity. Arch Gen Psychiatry 1989;46:81-87. 12. Irwin M, Daniels M, Bloom ET, Smith TL: Life events, depressive systems, and immune function. Am J Psychiatry 1987:144:4. 13. Dorian B, Garfinkel G, Brown G, Shore A, Gladman D, Keystone E: Aberrations in lymphocyte subpopulations and function during psychological stress. Clin Exp Immunol 1982;50: 132-138. 14. Kiecolt-Glaser JK, Garner W, Speicher C, Penn GM, Holliday J, Glaser R: Psychosocial modifiers of immunocompetence in medical students. Psychosom Med 1984;46:7-14. 15. Schleifer SJ, Keller SE, Siris SG, Davis KL, Stein M: Depression and immunity. Lymphocyte function in ambulatory depressed, hospitalized schizophrenic, and hemiorrhaphy patients. Arch Gen Psychiatry 1985;42:129. 16. Linn BS, Jensen JJ: Age and immune response to a surgical stress. Arch Surg 1983;221:568. 17. Clayton PJ, Halikes JA, Maurice WL: The depression of widowhood. Br J Psychiatry 1972;120:71. 18. Parkes CM: Bereavement: studies of Grief in Adult Life. New York, International Univ Press, 1972. 19. Odegard 0: The excess mortality of the insane. Acta Psychiatr Scand 1952;27:353-367. 20. Avery D, Winokur G: Mortality in depressed patients treated with electroconvulsive therapy and antidepressants. Arch Gen Psychiatry 1976;33:1029-1037. 21. Murphy JM, Monson RR, Olivier DC, Sobol AM, Leighton AH: Affective disorders and mortality. Arch Gen Psychiatry 1987;44:473-480. 22. Shekelle RB, Raynor WJ, Osfeld AM, Garron D, Bieliauskas L, Liv S, Maliza C, Paul 0: Psychological depression and 17 year risk of death from cancer. Psychosom Med 1982;43: 117-1022. 23. Cappel R, Gregoire F, Thiry L, Sprecher S: Antibody and cell mediated immunity to herpes simplex virus in psychotic depression. J Clin Psychiatry 1978;39:266-268. 24. Sachar EJ, Hellman L, Roffwarg HP, Halpem FS, Fukushima DK, Gallagher TF: Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Arch Gen Psychiatry 1973; 134:493-501. 25. Carroll BJ, Curtis GC, Mendels J: Neuroendocrine regulation in depression: II. Discrimination of depressed from nondepressed patients. Arch Gen Psychiatry 1976;33:1051-1058. 26. Deberdt R, Van Hooren J, Biesbrouck M, Amery W: Antinuclear factor-positive mental depression: a single disease entity. Biol Psychiatry 1976; 11:69-74. 27. Johnstone EC, Whaley K: Antinuclear antibodies in psy-
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chiatric illness: Their relationship to diagnosis and drug treatment. Br Med J 1975;2:724-725. 28. Shopsin B, Sathananthan GL, Chan TL, Kravitz H, Gershon S: Antinuclear factor in psychiatric patients. Biol Psychiatry 1973;7:81-86. 29. Kronfol Z, Silva J Jr, Greden J, et al.: Impaired lymophocyte function in depressive illness. Life Sciences 1983;33:241-247. 30. Schleifer SJ, Keller SE, Meyerson AT, Raskin MJ, Davis KL, Stein M: Lymphocyte function in major depressive disorder. Arch Gen Psychiatr 1984;41:484-486. 31. Spitzer RL, Endicott J, Robins E: Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry 1978;35:773-782. 32. Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967;136:4503-08. 32. Cohen J, Cohen P: Applied multiple regression/correlation analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ, Lawrence Erlbaum Associates, 1983. 33. Asnis GM, Sachar EJ, Halbreich V, Nathan RS, Novacenko H, Ostrow LC: Cortisol secretion in relation to age in major depression. Psychosom Med 1981;43:235-242. 34. Feldman RD, Limbird LE, Nadeau J, Robertson D, Wood JJ: Alterations in leukocyte Beta-receptor affinity with aging. A potential explanation for altered Beta-adrenergic sensitivity in the elderly. N Engl J Med 1984;310:815-819. 35. Siever LA, Davis KL: Toward a dysregulation hypothesis of depression. Am J Psychiatry 1985;142:1017-1031. 36. KocsisJH, DavisJM, KatzMM, etal.: Depressive behavior and hyperactive adrenocortical function. Am J Psychiatry 1985;142: 1291-1298. 37. Sachar EJ, Asnis G, Halbreich V, et al.: Recent studies in the neuroendocrinology of major depressive disorders. Psychiatr Clin 1980;3:313-326. 38. Cupps TR, Fauci AS: Corticosteroid-mediated immunoregulation in man. Immuno Rev 1982;65:134-155. 39. Cupps TR, Edgar LC, Thomas CA, Fauci, AS: Multiple mechanisms of B cell immunoregulation in man after administration of in vivo corticosteroids. J Immunol 1984;132:170-175. 40. Baumgartner A, Hahnenkamp L, Meinhold H: Effects of age and diagnosis on thyrotropin response to thyrotropinreleasing hormone in psychiatric patients. Psychiatry Res 1986;17:285-294. 41. Checkley S, Arendt J: Pharmacoendocrine studies of GH, PRL, and melatonin in patients with affective illness. In: Brown GM, Koslow SH, Reichlin S, eds., Neuroendocrinology and Psychiatric Disorder, New York, Raven Press, 1984; 165-190. 42. Rubin RT, Poland RE: Pituitary-adrenocortical and pituitary-gonadal function in affective disorder. In: Brown GM, Koslow SH, Reichlin S, eds., Neuroendocrinology and Psychiatric Disorder. New York, Raven Press, 1984;151-164. 43. Fabris N: Immunodepression in thyroid deprived animals. Clin Exp Immunol 1973;15:601-611. 44. Snow EC: Insulin and growth hormone function as minor growth factors that potentiate lymphocyte activation. J Immunol 1985;135:776s-778s. 45. Grossman CJ: Interactions between the gonadal steroids and the immune system. Science 1985;227:257-261. 46. Keller SE, Weiss JM, Schleifer Sd, Miller E, Stein M: Stress
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induced suppression of lymphocyte stimulation in adrenalectomized rats. Science 1983;221:1301-1304. 47. Miles K, Atweh S, Otten G, Armason BGW, ChelmickaSchorr: f3-adrenergic receptors on splenic lymphocytes from axotomized mice. Int J Immunopharmacol 1984;6: 171. 48. Hohlfield R, Toyka KV, Heininger K, Wilde HG, Kalies I: Autoimmune human T lymphocytes specific for acetylcholine receptors. Nature 1984;310:244. 49. Mann JJ, Brown RP, HalperJP, et al.: Reduced sensitivity of lymphocyte Beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation. N Engl J Med 1985;313:715-720. 50. Lake CR, Pickar D, Ziegler MG, Lipper S, Slater S, Murphy DL. High plasma norepinephrine levels in patients with major depressive disorder. Am J Psychiatry 1982;139: 1315-1318. 51. Roy A, Pickar D, Sinnoila M, Potter WZ: Plasma norepinephrine level in affective disorders. Relationship to melancholia. Arch Gen Psychiatry 1985;42:1181-1185. 52. Keller SE, Schleifer SJ, Stein M, Liotta AJ, Bond RN, Farhoody N: Stress-induced alterations of immunity in hypophysectomized rats. Proc Natl Acad Sci (USA) 1988;85: 9297-9301. 53. Dohrenwend BP, Shrout PE, Egr G, Mendelsohn FS: Measures of nonspecific psychological distress and other dimensions of psychopathology in the general population. Arch Gen Psychiatry 1980;37:1229-1236. 54. Dohrenwend BP, Shrout PE, Link BG, Martin JL, Skodol AE: Overview and initial results from a risk-factor study of de-
Anesth Prog 34:93-98 1990 pression and schizophrenia. In: Barrett JE, Rose RM, eds., Mental Disorders in the Community. New York: Guilford Press, 1986;184-215. 55. Gallagher RM, Marbach JJ, Cloitre M, Dohrenwend BP, Raphael KG: Is major depression co-morbid with temporomandibular pain and dysfunction syndrome?: A pilot study. Submitted. 56. Spitzer RL, Williams JBW, Gibbon M: Structured clinical interview 57. Workman EA, LaVia MF: T-Lymphocyte polyclonal proliferation: effects of stress and stress response style on medical students taking national board examinations. Clin Immunol Im-
munopath 1987;43:308-313. 58. Felten DL: Involvement of peripheral and central catecholamine systems in neural-immune interactions. Journal of Neuroimmunology 1985;10:5-30. 59. Morley JE, Kay NE, Solomon GF, Plotnikoff NP: Neuropeptides: Conductors of the immune orchestra. Life Sciences 1987;41:527-544. 60. Shavit Y, Lewis JW, Terman W, Gale RP, Liebeskind JC: Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity. Science 1984;223:188-190. 61. Weissman MM, Myers JK: Affective disorders in a U.S. urban community: The use of Research Diagnostic Criteria in an epidemiologic survey. Arch Gen Psychiatry 1978;35: 1304-1311. 62. Weissmann MM, Leaf PT, Holzer (III) CE, Meyers JK, Tischler GL: The epidemiology of depression: An update in sex differences in rates. J Affective Disorders 1984;7:179-188.
Psychoneuroimmunology: Chronic Orofacial Pain
Potenil Relevnce to
Steven J. Schleifer, MD,* Joseph Marbach, DDS,t Steven E. Keller, PhD* *University of Medicine and Dentistry of New Jersey, Newark, New Jersey; tColumbia University, New York, New York
patients with chronic pain,2 however, these states are characterized by a number of factors that are likely to be associated with altered immunity. Patients suffering with chronic pain often expenence high levels of stress, demoralization, and depression; they tend to use a variety of prescribed and selfadministered drugs that may alter immune processes; and they may also suffer from other systemic disorders that can alter the immune system.3 Pain states may be associated with changes in endogenous opioids, which are believed to be involved in immunoregulation, in addition to eliciting the use of exogenous opioids. This presentation will review psychoimmunologic studies from our laboratory and others suggesting that stress, depression, and the pain syndrome itself may have psychoimmunologic consequences in patients with chronic facial pain.
Studies undertaken over the past ten years have demonstrated that stress and depression can induce immune alterations, including decreased numbers of immunocompetent cells and impaired lymphocyte and natural killer cell activity. Factors such as age and severity of symptomatology influence these effects. The substantial stress and depression associated with chronic pain syndromes and the evidence for opioid involvement in immunomodulation suggest that immune system changes may occur in some patients with chronic facial pain.
There is increasing evidence that behavioral and psychological factors can influence the immune system and that these effects may contribute to the onset and course of disease.' These factors include exposure to stress, psychological symptoms or syndromes such as depression, and the use of alcohol, opioids, and other drugs. Psychoimmunologic changes may be the direct result of central processes mediated by neural and neuroendocrine systems, or may be effected behaviorally as by exposure to immunoactive chemicals or by changes in activity, sleep, or nutrition that can alter the immune system. Psychoimmunologic effects may be exaggerated or mitigated in patients with concurrent medical disorders that have immunologic effects.
LIFE STRESS AND IMMUNITY
That psychosocial processes influence immunity was suggested by studies demonstrating that the brain is involved in the regulation of the immune system. Evidence, derived primarily from lesion studies, have implicated the midbrain, the anterior hypothalamus, and the cerebral hemispheres in both T and B cell activity. Animal studies demonstrated that a variety of stressors can alter humoral (B cell) and cell-mediated (T-cell) immune responses.' Effects on both T and B cell functions are associated with characteristics of the stressor such as chronicity4 and intensity.5 Other research demonstrated influences of higher cortical function on immune processes. Laudenslager and Ryan6 presented evidence that stress-induced suppression of lymphocyte function is related to the animal's having control over the stressor. Ader and others' found conditioning effects on both humoral and cell-mediated immunity. These animal studies demonstrate that
Litfle is known conceming immunologic processes in
Address correspondence to Steven J. Schleifer, MD, Associate Professor, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Departnent of Psychiatry, 185 South Orange Avenue, MSB, E501, Newark, NJ 07103-2757. C 1990 by the American Dental Society of Anesthesiology
ISSN 0003-3006/90/$3.50
93
94 Psychoneuroimmunology and Chronic Pain
specific central nervous system (CNS) behavioral processes can influence the immune system. Research on life stress and immunity in man has identified several conditions in which altered, primarily suppressed immunity occurs. The death of a spouse was among the first life experiences investigated in relation to the immune system, as it is one of the most stressful commonly occurring events. Bereavement has also been linked to medical mortality.78 Bartrop and coworkers9 first reported alterations in the immune system in the bereaved. They found lower mitogen-induced lymphocyte stimulation in bereaved spouses compared with matched controls, suggesting that the functional capacity of the lymphocyte was altered in the bereaved. We investigated bereavement and immunity in a prospective study of healthy spouses of women with advanced breast carcinoma. 11 In vitro measures of immunity were obtained at 6 to 8-week intervals. The mean levels of mitogen-induced lymphocyte stimulation before death of a spouse were compared with that obtained during the first two months postbereavement and then during the latter part of the postbereavement year. Responses to the mitogens phytohemagglutinin (PHA), concanavalin A (ConA), and pokeweed mitogen (PWM) were significantly lower during the first two months postbereavement compared with those obtained prebereavement. By the end of the postbereavement year, mitogen responses had returned to prebereavement levels for the majority but not all of the subjects. Although individual mitogen data must be interpreted with caution due to the considerable day to day variability of the assays,11 our study suggested that there are differing response patterns among the bereaved. While many showed a greater than 50% suppression of mitogen responses postbereavement, several spouses showed little or no change soon after bereavement. The latter, however, had decreased mitogen responsivity later in the postbereavement year-when the majority of subjects were showing a return to prebereavement levels. This delayed response group tended to be younger, suggesting that age may be an important cofactor in psychoimmunologic processes. Altered nutrition, activity and exercise levels, sleep, and drug use, often found in the widowed, must also be taken into account, although our subjects did not report major changes in these parameters. Another important component of the immune system, natural killer (NK) cell activity, also has been found to be altered in relation to bereavement and related stress states. Irwin and coworkers'2 studied NK function in women experiencing a spouse's metastatic cancer and bereavement. They found lower NK activity in women who had experienced major stressful life experiences compared with women who had few life changes. The effects of more minor life stressors have also been
Anesth Prog 34:93-98 1990
investigated-with most studies of students undergoing academic examinations. Several studies'3'57 found altered mitogen responses in psychiatric residents and medical students during examination periods. Kiecolt-Glaser et al.'4 found lower NK cell function in medical students taking final examinations. In contrast, other moderate stressful conditions have not been found to alter immune measures. Both our group'5 and Linn and Jensen'6 found that otherwise healthy patients hospitalized for elective surgery did not show changes in lymphocyte mitogen responses when compared with controls. NK cell activity, however, which may be more sensitive to minor stress states, was not investigated in these studies, and research including a range of immunologic parameters in various stress conditions is needed.
DEPRESSION AND IMMUNITY
Changes in affective state, including the development of clinically significant depression, could be involved in the effects of bereavement and other stressors on immunity. Bereavement is associated with persistent changes in mood state and in appetite functions, sleep, and activity levels that often suggest the presence of clinical affective disorder.7",8 Depression, like bereavement, has been associated with increased medical mortality,'9-2' as well as with immune-related disorders.19'22'23 Furthermore, neuroendocrine functions that may influence immunologic processes are altered in many depressed patients.2425 Several studies have suggested that effects of life stress on immunity are associated with depressive reactions. The studies of Kiecolt-Glaser et al.'4 and Irwin et al.'2 both suggest that life stress results in greater immune suppression when affective disturbances are present. These observations suggest that depression may be a major factor in psychoimmunologic processes. Studies of immunity in patients with clinical affective disorders support this notion. Several reports have noted the presence of autoimmune markers in patients with depression.26-28 Studies of lymphocyte activity in depressed patients were first reported by Cappel and coworkers23 who found altered mitogen responses during the acute phase of depressive illness. Similarly, Kronfol and coworkers29 found lower mitogen responses in depressed patients than in psychiatric and normal controls. We investigated immune processes in medication-free subjects with major depressive disorder studied on the same day with age- and sex-matched controls. We found that hospitalized patients with major depression had significantly decreased numbers of circulating lymphocytes (T and B cells) and decreased lymphocyte mitogen responses (PHA, ConA, and PWM) compared with con-
Anesth Prog 34:93-98 1990 trols.30 To determine the specificity of these effects, we studied ambulatory patients with major depression15 and found that they did not differ from controls. This suggested that altered lymphocyte activity in depressed inpatients was related either to the severity of depression or to hospitalization itself. Studies of otherwise healthy hospitalized patients with schizophrenia and of subjects hospitalized for elective surgery,15 however, found no differences in mitogen response from controls indicating that hospitalization, per se, is not a determining psychoimmunologic factor. Linn and Jensen16 similarly did not find mitogen changes in otherwise healthy patients hospitalized for elective surgery. To further investigate the contribution of severity of depression, hospitalization, age, and gender, we more recently investigated a sample of 91 hospitalized and ambulatory major depressive disorder patients.1" This study used an expanded battery of immune functions and included patients across a range of ages, illness severity, and sex. As in prior studies, diagnoses of major depressive disorder were made using strict diagnostic criteria31 and the Hamilton Depression Rating Scale (HDRS)32 was used as the index of severity. Patients were studied on the same day with healthy age- and sex-matched controls. The assays included lymphocyte stimulation by the mitogens PHA, ConA, and PWM; quantification of the number of peripheral blood lymphocytes and lymphocyte subsets; and NK cell activity. The pooled sample of depressed patients did not differ from the matched controls (ANOVA) on any of the immune measures, indicating that altered immunity is not invariably characteristic of all patients with depression. Significant differences between patients and controls were revealed, however, when age, sex, severity of depression, and hospitalization were considered using hierarchical multiple regression techniques [analysis of partial variance (APV)32]. We found that the relationship between age and lymphocyte function was significantly different in the controls and the patients for each of the mitogens; a similar pattern of differences was found for the number of T4 (Thelper) lymphocytes. It appears that, with increasing age in the middle and later years, patients with major depression have specific concurrent deficits in the numbers of T4 cells and in lymphocyte stimulation responses; the altered T-helper cells may contribute to the lymphocyte functional changes. In contrast to older depressed patients, depressed young adults may have relatively increased T4 cells and lymphocyte activity. In addition, a significant effect of severity of depression on lymphocyte function across all ages was found. The age-related immune changes in depressed patients, and possibly following bereavement, may represent an interaction between processes associated with depression and those associated with aging. Suppressed mitogen re-
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activity in older and depressed patients may result from exaggerated neuroendocrine or autonomic nervous system changes in the older depressed patient33-35 imposed upon an immune system that has limited adaptive capacity due to immunosenescent processes. The age-related immune differences may also relate to differences in the depressive disorders found in younger and older patients. Our finding of a correlation between severity of depression and mitogen response, independent of age, suggest that at least some of the immunologic effects of depression are related to the state of depression. They are also consistent with an association between affective symptomatology and altered immunity, an effect that may be independent of syndromal status. Affective distress could therefore account for altered immunity both in depressive disorders and in stress-related states such as following bereavement.
MEDIATION OF IMMUNE CHANGES IN DEPRESSION AND FOLLOWING STRESS Depressive disorders are associated with changes in several neuroendocrine systems that can alter immune processes. Many of these systems are also altered in stress conditions and in pain states. Changes in the hypothalamic-pituitary-adrenal (HPA) axis following stress and in depression, some of which are age-related,33'36 have been demonstrated most consistently.25'36'37 Corticosteroids suppress lymphocyte proliferation38 and induce the redistribution of T-helper cells out of the peripheral blood.39 Abnormalities in the hypothalamic-pituitary-thyroid axis,"40 growth hormone,41 and sex steroids42 have also been demonstrated in depression, and each of these hormonal systems has been reported to modulate immune function.-45 Supporting the heterogeneity of neuroendocrine psychoimmunologic mechanisms are our findings in the rat, that there are both adrenal-dependent and adrenal-independent stress effects on the immune system.46 Alterations in immunity found in depression and other states may therefore involve diverse neuroendocrine processes. Influences other than those associated with classical neuroendocrine pathways may alter immunity in depression and following stress. Autonomic systems may be involved in modulation of immunity,47", and direct neural innervation of lymphoid tissue has been demonstrated.58 Dysregulated noradrenergic function in depression,35'49-51 which may be age-related' as may peripheral catecholamine output following stress, may contribute to altered immunity. We have found pituitary-independent changes in immunity in stressed hypophysectomized rats,52 providing additional evidence for multiple mechanisms in stressinduced immunomodulation. There is increasing interest in the potential role of pep-
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96 Psychoneuroimmunology and Chronic Pain
tides, especially the opioids, in the modulation of immunity. Endorphins are secreted together with ACTH in stress conditions and may play an important role in stress responses. Effects of endogenous opioids on immune processes have occasioned much interest; however, the research findings have been complex and at times inconsistent. Altered NK activity following exposure to opioid peptides may be age related and mediated via opioid receptors.59 In contrast, opioid effects on mitogen stimulation have been less consistently demonstrated and appear to be nonspecific. Shavit et al' have provided provocative evidence that opioids may be important modulators of immune changes following stressful conditions that are also "depressogenic." They found that, in rats, a stress paradigm inducing opioid-mediated analgesia and associated with leamed helplessness (an animal model of depression) resulted in suppressed NK function, whereas a stress paradigm mediated by nonopioid mechanisms was not NK suppressive. The opioids, as well as other peptides such as substance P,59 are of particular relevance to the study of immunity in patients with chronic pain as well as depression.
CHRONIC FACIAL PAIN, STRESS, DEPRESSION, AND IMMUNITY Chronic facial pain may provide an important model for the investigation of psychoimmunologic processes. Syndromes such as temporomandibular pain dysfunction syndrome (TMPDS) are associated with substantial functional morbidity, themselves act as stressors, and are marked by a state of pain that is not linked to systemic, hence potentially immunosuppressive, disease. The point of departure for the present research derived from striking findings in two of our prior studies on TMPDS patients. In the first study of 151 women with TMPDS and 139 healthy controls,3 TMPDS patients showed much higher levels of nonspecific distress, or demoralization. Demoralization is measured by 8 highly correlated symptom scales that include anxiety, sadness, poor self esteem, hopelessness-helplessness, dread, confused thinking, psychophysiological symptoms, and perceived physical health.53 The average score on the demoralization scale for the women with TMPDS (1.8 + 0.7) represented a score midway between the levels shown by the controls (1.1 + 0.5) and a comparable sample from another study of women psychiatric patients (mean = 2.5 + 0.7) who had had a recent episode of major depression.54 This suggested that some of the TMPDS women might meet criteria for a diagnosis of depression, indicating a comorbidity of TMPDS and depression. To investigate this possibility, a pilot study was conducted on a subsample of 20 of the TMPDS patients.55 DSM III-R diagnoses of current and lifetime depression
and other psychiatric disorders were obtained using a standardized semistructured diagnostic interview.56 Current (24%) and lifetime (69%) prevalence rates of depression among TMPDS cases (adjusted for sampling procedures) were much higher than those found in general population studies.61,62 These results suggest comorbidity of TMPDS and depression, with further descriptive and psychophysiological studies indicated. Chronic facial pain patients may therefore be at risk for alterations in immunity and possible secondary systemic morbidities. We recently initiated a study of immune function in women with TMPDS. The study was undertaken to investigate the psychoimmunologic effects of life stress and depressive reactions in patients with chronic facial pain, particularly in relation to potential interactions among the dimensions of pain, stress, and depression. Only patients otherwise in good health and not currently taking medications with demonstrated effects on the immune system have been included. This procedure tends to exclude the more severe TMPDS cases. Assessments of life stress, demoralization, and major depressive disorder have been conducted on 19 TMPDS patients and 19 age-sex matched controls. Blood for immunologic assessments was obtained from patients and their matched controls on the same day during the morning hours. Immunologic assays included quantitation of lymphocyte phenotypes and subtypes, mitogen-induced lymphocyte stimulation, and NK cell numbers and function. Preliminary analysis suggest that there are associations between demoralization and both mitogen-induced lymphocyte stimulation and NK activity. They suggest that changes in the immune system are found in some patients with chronic pain syndromes. The nature and extent of these effects require systematic investigation. REFERENCES 1. Ader R: Psychoneuroimmunology. New York, Academic Press, 1981. 2. Magni G: On the relationship between chronic pain and depression when there is no organic lesion. Pain 1987;31: 1-21. 3. Marbach JJ, Lennon MC, Dohrenwend BP: Candidate risk factors for temporomandibular pain and dysfunction syndrome: psychosocial, health behavior, physical illness and injury. Pain 1988;34:139-151. 4. Monjan AA, Collector MI: Stress-induced modulation of the immune response. Science 1977;196:307. 5. Keller SE, Weiss JM, Schleifer SJ, Miller E, Stein M: Suppression of immunity by stress: effect of a graded series of stressors on lymphocyte stimulation in the rat. Science 1981;213: 1397-1400. 6. Laudenslager ML, Ryan SM: Coping and immunosuppression: inescapable but not escapable shock suppresses lymphocyte proliferation. Science 1983;221:568. 7. Parkes CM, Benjamine B, Fitzgerald RG: Broken heart:
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