Laurence Bradley - US grants

The aim of the proposed study is to better understand the central factors involved in the etiopathogenesis of altered pain perception in fibromyalgia (FM). We will test six hypotheses drawn from a model which posits that neuroendocrine and immunologic abnormalities, characterized by decreases in cerebrospinal fluid (CSF) serotonin and increases in CSF substance P (SP), lead to sensitization of central nervous system structures involved in pain perception, i.e., thalamus and caudate nucleus. Decreases in regional cerebral blood flow (rCBF) to these structures serve as markers for this sensitization process and are associated with generalized low pain thresholds and other alterations in pain perception, independently of the effects of psychiatric morbidity or psychological status. The model also posits that elevated CSF SP may in part be due to SP messenger (m) RNA production by CSF leukocytes. We propose to measure (l) rCBF to cortex, thalamus, and caudate nucleus, (2) CSF levels of serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), SP, CSF leukocyte number, and leukocyte SP mRNA level, (3) pain thresholds and indices of sensory discrimination ability and response bias in response to dolorimeter stimulation of tender and control points, and (4) psychological status and number of lifetime psychiatric diagnoses. These variables will be assessed using (l) 80 patients with FM by American College of Rheumatology (ACR) criteria drawn from the Rheumatology clinics at UAB and Cooper Green Hospital ("Patients"), (2) 50 community residents of comparable age, gender, education, and race with musculoskeletal pain who fulfill ACR criteria for FM, but who have not sought medical care for their symptoms in the past 10 years ("Non-Patients"), and (3) 50 community residents of comparable demographic features without musculoskeletal pain who do not fulfill ACR criteria for FM ("Controls"). The use of non- patients, who do not differ from controls in psychiatric morbidity, will allow us to determine if altered levels of rCBF to the thalamus and caudate nucleus are associated with pain perception and neurochemical levels regardless of subjects' psychiatric histories. This study is the first to examine relationships among rCBF to central structures and neurotransmitters involved in pain perception and subjects' responses to noxious stimuli while controlling for psychological variables. The results of this study will advance our knowledge regarding the roles of the central nervous system and neuroendocrine and immunologic abnormalities involved in altered pain perception among patients and community residents with FM. In addition, the results of the project may lead to development of pharmacologic interventions that will normalize rCBF to central brain structures and thus decrease pain among patients with FM.

Approximately 75,000-150,000 patients each year in the United States are identified as suffering from chest pain of unknown etiology (CP). These patients have excessive levels of disability and account for $250,000,000- $500,000,000 in estimated health care costs each year. There are no standard treatment protocols that have been shown to reliably improve these patients' pain and disability and to reduce their excessive health care utilization, although there is some evidence that regimens of imipramine and cognitive-behavioral therapy may produce short-term reductions in pain intensity. We propose to perform the first 16-week randomized controlled outcome study of these interventions in which 160 CP patients will be assigned to one of four treatment conditions: cognitive- behavioral therapy (CBT), attention-placebo social support intervention, pharmacologic (imipramine) therapy, or pharmacologic placebo. Assessments will be performed at baseline, post-treatment, 6-month follow-up, and 12- month follow-up to evaluate the short and long term efficacy of the interventions. Dependent variables will consist primarily of measures that we have found to distinguish CP patients from patients with other painful gastrointestinal disorders and from healthy controls: clinical pain intensity, pain thresholds and response bias for esophageal balloon distension, coping strategies, self-efficacy, and spouse response to patients pain behavior. Health care utilization and disability also will be assessed to evaluate changes in patients' quality of life. We will test 7 specific hypotheses involving comparisons of CBT and pharmacologic therapy in improving pain and quality of life among CP patients. This study also will be unique in- that it will determine whether one or both of our experimental treatments influence the factors that underlie altered pain perception and symptom reports among CP patients (i.e., pain threshold and response bias levels). Finally, this is the first outcome study of treatments for patients with CP that will evaluate whether patients maintain their improvements for 12 months following treatment and that will evaluate clinical, as well as statistical significance of treatment effects.

We propose two studies with the aim of better understanding the role of inhibited functional brain activity (assessed by regional cerebral blood flow [rCBF]) and abnormal pain perception in the etiopathogenesis of fibromyalgia (FM). To accomplish this aim, we will test six hypotheses based on an etiopathogenetic model of FM developed in our laboratory. Specifically, we wish to determine whether: (a) functional brain activity in the thalamus and caudate nucleus during resting conditions and behavioral indices of pain perception reliably distinguish FM patients from patient with chronic fatigue syndrome (CFS) or major depression and healthy controls; and (b) FM patients differ from the three comparison groups with respect to changes in functional brain activity in the thalamus, caudate nucleus, appropriate somatosensory cortices, and anterior cyngulate gyrus upon exposure to painful dolorimeter stimulation. We will recruit (a) 30 patients with primary FM by American College of Rheumatology (ACR) criteria; (b) 30 patients with CFS by Centers for Disease Control criteria who are pain-free and do not meet ACR criteria for FM; (c) 30 patients with current major depression who are pain-free and do not meet criteria for other current psychiatric diagnoses or criteria for FM or CFS; and (d) 30 healthy controls who are pain-free and do not meet criteria for FM or CFS. Patients will be recruited from appropriate UAB outpatient clinics and controls will be recruited from the Birmingham community. All subjects will be right-handed women. We propose to measure (a) pain thresholds for dolorimeter stimulation of 5 paired ACR tender points as well as behavioral indices of sensory discrimination ability and response bias; (b) rCBF using single photon emission computed tomographic (SPECT) imaging; and (c) responses to questionnaire measures of anxiety, depression, and pain as well as a structured psychiatric interview. The proposed studies represent an advance in the study of FM since they include the use of an experimental manipulation as well as correlational studies to evaluate an etiopathogenetic model of FM. The results also will help us to better understand the mechanisms responsible for inhibited functional brain activity observed in FM patients during resting conditions.

The overall goal of the proposed project is to better understand the pain and psychosocial factors that may be associated with status as a patient or non-patient among persons with fibromyalgia (FM). To accomplish this goal, the proposed project will use longitudinal as well as cross-sectional comparisons of pain perception and psychosocial variables among three subject groups. These three groups are: a) patients drawn from the UAB Rheumatology Clinic who have sought medical treatment for FM; b) age-, education-, and gender-matched persons sampled from the Birmingham community who meet the criteria for FM but who have not sought medical care for their symmptoms (i.e., FM non- patients); and c) age-, education-, and gender-matched healthy controls sampled from the Birmingham community.

There is substantial evidence of abnormal pain sensitivity and functional brain activity in patients with fibromyalgia (FM). It has been suggested that FM may be a stress-related disorder, given the evidence of abnormal function of the neuroendocrine axes and the tendency of stress to exacerbate FM symptoms. However, no investigator to date has examined the effects of stress on pain sensitivity or functional brain activity in FM patients and controls. We propose study to test 10 hypotheses derived from our model of abnormal pain perception in FM regarding the effects of stress on pain sensitivity and functional activity in brain structures that process pain. We will assess the effects of noxious thermal stimulation and personally relevant, stressful imagery on pain thresholds and tolerance, magnitude estimates of sensory intensity and unpleasantness, and functional activity of brain structures that process the sensory and affective dimensions of pain. We will perform these evaluation procedures with 120, non- depressed, right-handed women with FM and 60, non-depressed, healthy control women. The patients will be classified in one of two groups according to symptom onset (traumatic vs. insidious). We hypothesize that during noxious thermal stimulation, patients, compared to controls, will (a) produce higher ratings of pain intensity and unpleasantness; and (b) show an abnormal pattern of brain activation characterized by bilateral increases in regional cerebral blood flow (rCBF) in the somatosensory cortices and increases in the ipsilateral anterior cingulate (AC) cortex. We also hypothesize that during exposure to personally relevant, stressful imagery, patients, compared to controls will show (a) smaller increases in salivary cortisol; and (b) greater increases in blood pressure, pulse rate, thermal pain intensity and unpleasantness ratings, and thermal pain-induced change in the contralateral and ipsilateral somatosensory cortices as well as in the ipsilateral AC cortex. This study will allow us to assess the effects of stress on pain perception and functional brain activity in patients with FM independently of the influence of affective disorders. The results will advance our knowledge regarding the effects of stress on abnormal pain sensitivity and the biologic processes that underlie this sensitivity in persons with FM. Thus, the results of the study may eventually lead to improved pharmacologic inteventions that may normalize the central biologic abnormalities that produce painful symptoms in FM.

chronic pain; stimulus /response; autonomic nervous system; fibromyalgia; neural information processing; anxiety; cingulate gyrus; blood pressure; brain circulation; heart rate; patient oriented research; electromyography; human subject; clinical research;

chronic pain; human therapy evaluation; analgesia; sex hormones; nervous system disorder chemotherapy; pentazocine; morphine; fibromyalgia; patient oriented research; human subject; clinical research;

disease /disorder etiology; perception; pain; fibromyalgia; pathologic process; substance P; caudate nucleus; hydroxyindoleacetate; thalamus; brain circulation; cerebrospinal fluid; behavioral /social science research tag; human subject; clinical research;

psychological stressor; physiologic stressor; racial /ethnic difference; sensory feedback; pain threshold; heat stimulus; patient oriented research; clinical research; caucasian American; human subject; African American;

genetic susceptibility; chronic pain; serotonin transporter; family genetics; fibromyalgia; gender difference; heat stimulus; genetic promoter element; genetic polymorphism; patient oriented research; siblings; human subject; clinical research;

Pain associated with knee osteoarthritis (OA) is characterized by (a) high levels of variability among individuals;and (b) modest associations with radiographic measures of tissue damage. Ethnic background is one important factor that contributes to variation in pain reports and pain-related behavior. Recent studies indicate that African-American, compared to white, individuals exhibit lower pain tolerance levels and relatively impaired pain regulatory mechanisms (e.g., blood pressure responses to stressors). There also is evidence that endogenous opioid release contributes to the function of these mechanisms. The overall aim of the proposed study, then, is detemine whether changes in opioid neurotransmission evoked by thermal heat stimulation partially mediate ethnic differences in thermal pain responses among patients with knee OA. Thirty-six men (18 African-American, 18 white) with knee OA will undergo PET bain imaging with the opiodergic radioligand [18F] fluoroethyl-diprenorphine under two conditions: (a) exposure to thermal heat stimulation, tailored to individual pain thresholds, that will produce similar, moderate, levels of thermal pain intensity across patients;and (b) exposure to thermal heat stimulation that will produce perceptions of warmth across patients (sensory control condition). Patients will produce visual analogue scale (VAS) ratings of pain intensity and unpleasantness following stimulation. We expect that African-American, compared to white patients, will (a) produce significantly greater increases in pain unpleasantness ratings;and (b) exhibit lower opioid neurotransmission in medial pain system structures (e.g., amygdala, anterior cingulate cortex) from sensory control to painful thermal heat stimulation, even after controlling for psychosocial variables such as depressive symptom levels. We also expect that stimulation-evoked change in opioid neurotransmission in medial pain system structures will partially mediate the ethnic group difference in change in pain unpleasantness ratings. We anticipate that the proposed research will generate new sttudies that will lead to (a) improved understanding of additional physiologic or psychosocial variables that contribute to ethnic differences in pain responses and endogenous pain regulatory function;(b) development of new or refinement of current pharmacologic or behavioral/psychosocial interventions for pain management;and (c) reductions in ethnic disparities in patients'expectations of and preferences for these interventions.