1. Psychosomatic Medicine: Dealing with Stress and Pain

3. PSYCHONEUROIMMUNOLOGY The concept of a stress response: Physical or psychological stress alters the body's neuroendocrine systems. Responses are attempts to successfully cope with stress. When stress is severe or chronic, the altered physiology can cause or exacerbate health problems. Holmes life stress scale: statistical association between stress and numerous illnesses. Negative events are more detrimental than positive ones. Selye's general adaptation syndrome: Endocrine response to acute and chronic stress. Stress and disease: immune system cells both synthesize and respond to ACTH and beta- endorphins. Ader: Conditioned immunosuppression in rodents; conditioned immunoactivation. Pairing exposure to immunoactivators or immunosuppressors with smells. Chronic stress reduces a variety of immune indices in humans. (Glaser & Kiecolt-Glaser) Chronic stress decreases resistance to infectious diseases in mice (Ader).

4. Thomas Holmes Social Readjustment Rating Scale Journal of Psychosomatic Research 11:216, 1967

5. Grant Proposal ->

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7. Average M1 Day -> Grant Proposal -> Board Exam ->

8. Doctors have long recognized that stress can trigger a range of illnesses, from backache and headache to gastrointestinal problems and a weak immune system. Now you can estimate your risk of stress-related illness using this calculator developed by Dr Richard Rahe, a world- renowned expert on stress-related illness. As you can see below, the test assigns a measurement called the Life Change Unit (LCU) to events - positive and negative - that can cause stress. The higher your LCU total, the greater your risk of stress-related illness. NEW ADDITIONS BY RAHE; USE FOR BOARDS (incomplete list) Death of a child123 Death of a spouse119 Death of parent or sibling 101 Divorce 96 Separation from spouse due to work or marital difficulties 79 Being held in jail 75 An illness or injury that was: Very serious74 Moderately severe44 Less serious than above 20 Loss of your job74 Death of a close friend70 Pregnancy67 Miscarriage or abortion65 Major business readjustment or loss of income60 Credit difficulties56 Marriage (anchor) 50 Birth of a grandchild43 Beginning or ending school 38 Change in political beliefs 24 Change in religious beliefs 29 Minor violation of the law 20

9. PSYCHONEUROIMMUNOLOGY The concept of a stress response: Physical or psychological stress alters the body's neuroendocrine systems. Responses are attempts to successfully cope with stress. When stress is severe or chronic, the altered physiology can cause or exacerbate health problems. Holmes life stress scale: statistical association between stress and numerous illnesses. Negative events are more detrimental than positive ones. Selye's general adaptation syndrome: Endocrine response to acute and chronic stress. Stress and disease: immune system cells both synthesize and respond to ACTH and beta- endorphins. Ader: Conditioned immunosuppression in rodents; conditioned immunoactivation. Pairing exposure to immunoactivators or immunosuppressors with smells. Chronic stress reduces a variety of immune indices in humans. (Glaser & Kiecolt-Glaser) Chronic stress decreases resistance to infectious diseases in mice (Ader).

10. Minutes to hours Hours to indefinite Prolonged exposure to stage of resistance is chronic stress

11. H. Selye: General Adaptation Syndrome: Stress reaction has 3 stages, Alarm, Resistance and Exhaustion. Stress disorders represent reaction to chronic involvement in stage of resistance, "wearing down." Exhaustion may characterize late stages of a terminal diseases such as malignancy. Selye: *Eustress(+)e.g., physical exercise *Distress(-)e.g., environmental pressures Lazarus emphasized coping vs. vulnerability as a key dimension as to whether stress resulted in stress disorders.

12. Stress v Neural Activation - Hypothalamus v Secretion of Corticotrophin Releasing Factor (CRF) v Pituitary Release of Adrenocorticotrophic Hormone (ACTH) v Adrenal Release of Glucocorticoids v Metabolic, Immunological, Psychological Responses

14. Glucocorticoids from adrenal cortex Gluconeogenesis (from protein) Suppressed inflammation Immunosuppression decreased lymphocyte response impaired natural killer cell function Feedback to brain (esp Hippocampus)

15. STRESS AND DISEASE - Ia Peptic Ulcers:For years there was an established relationship between peptic ulcers (and other GI irritative diseases) and psychological stress.Marshall and Warren “Unidentified curved bacilli in the stomach of pts with gastric and peptic ulceration” (Lancet, 1984)Very tight causal relation between Helicobacter pylori and peptic ulcer and other irritative GI diseases.Diagnosis of infection (serology, IGG for H.p.; or endoscopy-biopsy), treat with antibiotics (tetracycline, metronidazole), is eradicating H. pylori infection in much of US population So What Happened to the Relationship to Stress?

16. STRESS AND DISEASE - Ib Evidence for a Relationship Between Stress and Ulcers:Gastric fluids increase acidity in response to anger, hostility, resentment, guilt, frustration.Stressful situations (surgery, school exams) increase basal gastric acid secretion.Alleviation of stress can reverse peptic ulcer condition.Animals exposed to stress develop stomach ulcers.Ulcer occurs in the absence of H. pylori infection.Most people still have H. pylori infection and do not have ulcers.Ulcer patients more likely to exhibit excess stress (Levenstein & Veylan, J. Clin. Gastroenterol., 1995).Psychological stress impedes ulcer healing.Other factors also important: sex (choose female), blood type (avoid O), other genetics, cigarettes, coffee, alcohol consumption patterns, possibly diet. These are not correlated with presence or degree of H. pylori infection.“Psychosomatic” etiology is preferentially discarded as soon as a “biological” explanation becomes available.

17. STRESS AND DISEASE - Ic Aside from Impaired Treatment of Pts and Widespread Overprescription of Antibiotics, are there Costs? On the Horizon:Absence of H. pylori infection may be linked to gastroesophogeal reflux disease (“acid reflux”; Labenz et al., Gastroenterology, 1997)Reflux disease increases risk for gastric adenocarcinoma, a serious form of malignancy, which has recently also been linked by co-occurrence to absence of H. pylori infection.H. pylori infection is dropping, especially among SES levels with good medical care.Stay tuned. And don’t throw out good data just because something more “biological” comes along. Consider the whole patient, both in theory and in practice.

18. STRESS AND DISEASE Id Coronary Artery Disease (Leading US cause of death; 1,250,000 heart attacks/year): Type A behavior? (Time urgency, competitive achievement orientation, anger hostility). Controversial, particularly in details, hostility may be most predictive of CAD. Stress can increase serum cholesterol levels. Sudden Cardiac Death: Heart arrhythmias may be associated with chronic stress (animal and human studies) Clear evidence for stress as cause or contributing factor in many human clinical cases Learned Helplessness (Seligman): Controllable vs. uncontrollable life events; uncontrollable events lead to feelings of helplessness Sense of personal control of one’s life leads to greater self-efficacy, “hardiness” May be a model for depression

19. STRESS AND DISEASE IIb Hypertension (incidence: 25-38% of adults); major risk factor for cardiac and brain disorders:Chronic stress leads to hypertension in animal studiesHuman studies suggest greater tendency towards hypertension with stress. Stressful occupations: Air traffic controllers have exceptionally high prevalence of hypertension Cancer:Rats subjected to stress less likely to reject tumor implantsWomen who respond poorly to stress: cervical cancer incidence higher; increased incidence of malignacy in breast biopsiesDepressed mood linked to increased cancer risk

20. STRESS AND THE IMMUNE SYSTEM Stress and disease: immune system cells both synthesize and respond to ACTH and beta-endorphins. Ader: Conditioned immunosuppression in rodents; conditioned immunoactivation. Pairing exposure to immunoactivators or immunosuppressors with smells. Stress Impairs Resistance to Infection in Laboratory Animals (Ader)

21. STRESS AND THE IMMUNE SYSTEM Evidence that Psychological Stess Affects Human Immune Function (Kiecolt-Glaser & Glaser, 1987) *Men whose wives had died of breast cancer had decreased immune function *Marital disruption is associated with increased morbidity and mortality *Divorced people more likely to die from pneumonia than married people *Women who are separated have 30% more appointments for physical illness *Patients with mental illness have greater numbers of physical illnesses *Medical students have reduced immune function (Natural Killer Cell activity) during final exams

22. STRESS AND PSYCHIATRIC ILLNESS *Social stressors often associated with depression *Other medical illnesses increase probability of psychiatric disorders by about 1/3 *Posttraumatic stress disorder: often see loss of affect, withdrawal, other signs of depression, some violent hostile behavior patterns, etc. *Kindling theory of depression (like kindled seizures) *Up to four-fold increase in incidence of psychiatric symptoms in people with high stress levels and poor coping skills vs. people with low stress levels, good coping skills

23. STRESS AND THE BRAIN Aging memory disorders - non-Alzheimer or other dementias. Associated with hippocampal neuron loss Animal model: Chronic stress or glucocorticoid exposure Stress induces: –Neuron loss in hippocampus (esp. region CA1) (Sapolsky) –Adrenalectomy induces hippocampal granule cell loss (Sloviter) –Individual stress history, indicated by adrenal weight, predicts hippocampal pyramidal cell loss with aging (Landfield)

24. Mechanism (?) (Sapolsky) –Glucocorticoids disrupt hippocampal glucose utilization. This leaves neurons vulnerable to insults. –Glucocorticoid administration sensitizes the hippocampus to epilepsy or hypoxia –Glucose supplements protect the hippocampus –Likewise, monkeys that died from ulceration had more hippocampal neuron loss than those that did not. Early Handling protects against stress-induced neuron loss BOTTOM LINE: STRESS AFFECTS THE BRAIN, AND THE WRONG KIND OF STRESS AFFECTS IT NEGATIVELY. THE ANSWERS ARE FAR FROM ALL IN, AND AS A PHYSICIAN, CONTINUING TO EDUCATE YOURSELF ABOUT THIS WILL BE IMPORTANT. STRESS AND THE BRAIN (Continued)

25. NEW TOPIC: PAIN ACUTE PERIPHERAL PAIN (You will get again in Neuro course) (Not required for exam) Epidermal Pain: c-fiber activation by intense physical stimulation Injurious tissue damage --> bradykinin (peptide), which in turn activates c-fibers c-fibers: small, unmyelinated somatosensory fibers that innervate epidermis, striated muscle, joints, etc. *most senstive to local anesthetics *interact with other sensory input to amplify pain sensation Opiate systems in spinal cord react to diminish this type of pain within a few minutes. This system subserves acute pain.

26. ACUTE PERIPHERAL PAIN (Not required for exam) Anti-opiates such as naloxone may increase pain, revealing effects of the body’s opiate systems. Placebo (“sugar pill”) administration may sometimes cause activation of opiate systems if subjects believe the pills are painkillers. Naloxone-sensitive pain reduction. Psychological activation of endogenous opiate systems. However, acute pain can modify central systems on a longer term basis. It is now commonly recommended that both peripheral “local” anesthetization and global anesthetic administration be used in conjunction with pain-inducing surgical procedures. Repetitious activation of C fibers builds up the electrical response of neurons to which they project in the spinal cord. This resembles LTP, a process thought to be involved in memory.

27. According to S. Siegel, an addict can take a dosage of heroin that would kill a person not used to it. But in fact, if the dosage is administered to the addict when he is unaware of it, it can kill the addict as well. Behavioral tolerance (to be described if time allows) suggests that conditioning affects the response to drugs. A rat can tolerate a larger dosage of an opiate if it is used to getting the opiate in a particular setting. Alternating injections, water and alcohol. Alcohol reduces body temperature. If all alcohol injections occur in one room and water injections in another, animals “defend” body temperature against alcohol. Addictions can also be dependent on context. Leaving an environment can leave drug addictions behind (e.g., Vietnam veterans). Reinstating environmental conditions can cause feelings of withdrawal. S. Siegel et al., Heroin overdose death: contribution of drug-associated environmental cues. Science, 216: 436-7, 1982

28. CHRONIC PAIN Chronic Pain: Basis is often much less clear. Incidence: more than 40% of the population will experience pain at some time in their lives. Chronic pain is not merely persistent acute pain. It may occur in the absence of obvious peripheral or visceral pathology. All pain has both sensory and affective-evaluative components. Focusing exclusively on either of these alone is equally misguided. With chronic pain there is not a linear relationship between nociception and pain experience. In chronic pain syndromes, there are qualitative differences in the affective-evaluative perception of pain. Prevalence of chronic pain increases with age

29. Sources of Chronic Pain Chronic Benign Pain: Any pain resulting from nonmalignant causes that is not allieviated by appropriate medical, pharmacotherapy, or surgical treatment. Example: Fibromyalgia, widespread aching, local tenderness, absence of laboratory evidence of inflammation. American College of Rheumatology defines as involving 3 or more segments of the body and at least 11 of 18 “tender points.” (e.g., trapezius, rib junctions, buttocks, knees) Steroids and NSAIDS have no more effect than placebo. (Placebos benefit 50% of patients, at least short-term.) Ketamine (NMDA receptor antagonist) appears to be effective in 50% of patients. Some think fibromyalgia is one extreme on a continuum of widespread chronic pain syndromes. Higher incidence in females. Opiates remain the most effective medications for managing chronic pain.

30. Behavioral Approaches to Chronic Pain Management It was historically thought that chronic pain patients exaggerated trivial pain problems-- not made of “the right stuff.” This is not therapeutically helpful. Goal is restoration of functional life. Chronic pain can have secondary consequences: depressive illness, marital discord, job problems social withdrawal, sleep disorders. Biofeedback therapies combine feedback from detectors such as muscle EMG electrodes with techniques such as muscle relaxation to affect muscle function. Biofeedback can be effective for muscle contraction headaches, for symptoms of chronic stress such as anxiety, and for blood pressure disorders such as hypertension. Controlling pain behavior through operant conditioning and other behavioral approaches has also had success. The approach focuses upon modifying pain-related behavior separately from the treatment of the pain itself. Exercise and conditioning (e.g. stretching) is a very important mitigator of increased chronic pain with aging. Mild joint and limb pain is very common in sedentary (inactive) aging people.

31. Gate Control theory of Pain (Melzack): the interpretation of sensation as painful depends on the relative amounts of large fiber vs. small fiber (c-fiber) activity. Propose stimulating large fibers. Works for some pts, not all. (This has been on Board exams) Chronic treatment with normally addictive drugs such as opiates is not as addictive as expected if the withdrawal of the opiate accompanies mitigation of the pain due to recovery or some other form of treatment. The addictions are often context-dependent and, if the context, chronic pain, goes away, the addiction may do likewise. Pain increases in incidence in elderly. Physicians may dismiss as “just a part of growing old.” This is age discrimination and not appropriate. Physician should make every attempt to diagnose and treat the pain.

33. A cat dies and goes to Heaven. God meets him at the gate and says, 'You have been a good cat all of these years. Anything you desire is yours, all you have to do is ask.' The cats says, 'Well, I lived all my life with a poor family on a farm and had to sleep on hardwood floors.' God says, 'Say no more.' And instantly, a fluffy pillow appears.

34. A cat dies and goes to Heaven. God meets him at the gate and says, 'You have been a good cat all of these years. Anything you desire is yours, all you have to do is ask.' The cats says, 'Well, I lived all my life with a poor family on a farm and had to sleep on hardwood floors.' God says, 'Say no more.' And instantly, a fluffy pillow appears. A few days later, 6 mice are killed in a tragic accident and they go to Heaven. God meets them at the gate with the same offer that He made the cat. The mice said, 'All our lives we've had to run. Cats, dogs and even women with brooms have chased us. If we could only have a pair of roller skates, we wouldn't have to run anymore.' God says, 'Say no more.' And instantly, each mouse is fitted with a beautiful pair of tiny roller skates.

35. A cat dies and goes to Heaven. God meets him at the gate and says, 'You have been a good cat all of these years. Anything you desire is yours, all you have to do is ask.' The cats says, 'Well, I lived all my life with a poor family on a farm and had to sleep on hardwood floors.' God says, 'Say no more.' And instantly, a fluffy pillow appears. A few days later, 6 mice are killed in a tragic accident and they go to Heaven. God meets them at the gate with the same offer that He made the cat. The mice said, 'All our lives we've had to run. Cats, dogs and even women with brooms have chased us. If we could only have a pair of roller skates, we wouldn't have to run anymore.' God says, 'Say no more.' And instantly, each mouse is fitted with a beautiful pair of tiny roller skates. About a week later, God decides to check and see how the cat is doing. The cat is sound asleep on his new pillow. God gently wakes him and asks, 'How are you doing? Are you happy here?'

36. A cat dies and goes to Heaven. God meets him at the gate and says, 'You have been a good cat all of these years. Anything you desire is yours, all you have to do is ask.' The cats says, 'Well, I lived all my life with a poor family on a farm and had to sleep on hardwood floors.' God says, 'Say no more.' And instantly, a fluffy pillow appears. A few days later, 6 mice are killed in a tragic accident and they go to Heaven. God meets them at the gate with the same offer that He made the cat. The mice said, 'All our lives we've had to run. Cats, dogs and even women with brooms have chased us. If we could only have a pair of roller skates, we wouldn't have to run anymore.' God says, 'Say no more.' And instantly, each mouse is fitted with a beautiful pair of tiny roller skates. About a week later, God decides to check and see how the cat is doing. The cat is sound asleep on his new pillow. God gently wakes him and asks, 'How are you doing? Are you happy here?' The cat yawns and stretches and says, 'Oh, I've never been happier in my life. And those Meals on Wheels you've been sending over are the best!'

37. The following slides provide a complete view of the “life stress index” as updated by Rahe. This material is not required. However, questions about the Holmes index and life stress index have appeared on the Part I Medical Board Exam

38. Life Stress Index by Rahe: Doctors have long recognized that stress can trigger a range of illnesses, from backache and headache to gastrointestinal problems and a weak immune system. Now you can estimate your risk of stress-related illness using this calculator developed by Dr Richard Rahe, a world-renowned expert on stress-related illness. The test assigns a measurement called the Life Change Unit (LCU) to events - positive and negative - that can cause stress. The higher your LCU total, the greater your risk of stress-related illness. Health

39. An illness or injury that was: Very serious74 Moderately severe44 Less serious than above20 Work Change to a new type of work51 Change in your work conditions35 Taking courses to help you18 Troubles at work32 Major business readjustment60 Loss of your job74 Retirement52 Home and Family Change in residence40 Major change in living conditions42 Change in family get-togethers25 Major change in health or behavior of a family member55 Marriage50

40. Pregnancy67 Miscarriage or abortion65 Birth (or adoption) of a child66 Spouse begins or stops work46 Change in arguments with spouse50 Problems with relatives or in-laws38 Parents divorce59 A parent remarries50 Separation from spouse due to work or marital difficulties79 Child leaves home42 Relative moves in with you59 Divorce96 Birth of a grandchild43 Death of a spouse119 Death of a child123

41. Death of parent or sibling101l and Social Change in personal habits26 Beginning or ending school38 Change of school or college35 Change in political beliefs24 Change in religious beliefs29 Change in social activities27 Vacation24 New, close, personal relationship37 Engagement to marry45 Personal relationship problems39 Sexual difficulties44 An accident48 Minor violation of the law20 Being held in jail75 Major decision about your future51 Major personal achievement36 Death of a close friend70l Major loss of income60 Major increase in income38 Loss/damage to personal property43 Major purchase37 Minor purchase20 Credit difficulties56

42. Vioxx (Rofecoxib) is a nonsteroidal anti-inflammatory drug (NSAID) that is used to treat pain, particularly the pain ofosteoarthritis and menstrual cramps. Prostaglandins are chemicals that are important in promoting inflammation and its signs--pain, fever, swelling and tenderness. Rofecoxib blocks the enzyme that makes prostaglandins (cyclooxygenase- 2) and thereby reduces the amounts of prostaglandins. As a consequence, inflammation and its accompanying pain, fever, swelling and tenderness also are reduced. Rofecoxib is similar to celecoxib (Celebrex). Both drugs differ from other NSAIDs in that they cause less irritation and ulceration of the stomach and intestine (at least during short-term treatment), and they do not interfere with the clotting of blood. Vioxx