Lonnie Zeltzer - US grants

Since medical procedures and chemotherapy cause major problems for a majority of children with cancer, even producing noncompliance with treatment for some, the objectives of this study are: (1) to determine if hypnosis is more effective than nonhypnotic intervention in reducing acute pain and anxiety related to medical procedures in children; (2) to compare hypnosis, supportive counseling, and assessment alone (control group) in their effectiveness in reducing nausea and vomiting in children and adolescents receiving cancer chemotherapy; (3) to determine if symptom reductions achieved with intervention are maintained after termination of intervention; and (4) to determine if hypnotic susceptibility is related to the degree of symptom reduction for patients receiving hypnosis. Pain and anxiety will be assessed in children (5-10 years) using patient (pt.) and observer (obs.) ratings and a behavioral checklist during 2 bone marrow aspirations and/or 2 lumbar punctures prior to intervention. Pts. (45-60) will be randomized to a hypnosis, supportive counseling, or control group and 2 more procedures will be assessed. For the second study, the duration (hours) and severity (pt. and parent ratings) of nausea (N), vomiting (V), and the extent to which these symptoms bother children (ages 5-21 years) will be assessed within 3-5 days after each of 2 courses of chemotherapy. Forty-five to 60 patients with N and V will be randomized to a hypnosis, supportive counseling, or control (assessment alone) group and the above data will be obtained during 4 more courses (matched with baseline courses for each pt.); pts. in the first 2 groups will receive intervention for the 2 courses after baseline. Mean pt. ratings of N, V, and bother for each time period for the 3 comparison groups will be analyzed by 3 x 3 ANOVA with repeated measures for time. A Friedman ANOVA will test the null hypothesis that no changes in duration of symptoms occurred over time. Comparisons across groups for each of the 3 time periods will be made using Kruskal-Wallis ANOVA's. Reliability checks on pt. ratings will be made by comparisons (Pearson's r) with parent ratings. Hypnotic susceptibility scores will be divided at the median and compared (2 x 2 chi-square) to change scores for pain and anxiety and for N and V. The overall significance of this study is to decrease the suffering of children with cancer and perhaps to improve survival by decreasing noncompliance with treatment.

A pediatric psychologist, a behavioral pediatrician, and a pediatric oncologist working as a team will study children and adolescents with cancer to determine: (1) the relative efficacy of hypnosis, supportive counseling and assessment alone on the reduction of chemotherapy-related nausea and vomiting, (2) if any beneficial effects achieved with active therapist-directed intervention are maintanined by the patient without the therapist, and (3) the relationship between hypnotic susceptibility and symptom reduction for those patients receiving hypnotic intervention. Patients' and parents' ratings of the severity of nausea and vomiting and the duration of these symptoms, including disruption of eating, sleeping, school, and activities, will be obtained immediately following each of two matched (for drug types and dosages) consecutive courses of chemotherapy for 45-60 patients (5-21 years of age). Patients with nausea/vomiting will be randomized to one of three groups: hypnosis, supportive counseling, and a no-treatment control. The groups will be matched at baseline for age and severity of nausea and vomiting. Patients in the first two more courses will be assessed without intervention. The control group will have all four courses assessed without intervention. Nurses who administer the chemotherapy will document anticipatory emesis in the clinic. Mean ratings of nausea and vomiting during each time period will be analyzed by a 3 (groups) x 3 (time periods) analysis of variance with repeated measures for time for each variable. Mean duration of nausea, vomiting, and disruption of eating, sleep, school, and activities during each of the 3 time periods will be analyzed by a Friedman analysis of variance (separately for the 3 groups) to determine if changes occurred over time. Comparisons across groups for each of the 3 times periods will be made by a Kruskal-Wallis analysis of variance. Parental and patients' ratings of severity of nausea and vomiting will be correlated (Pearson's r). If the frequency of anticipatory emesis changes for any of the groups, then the 3 groups would be compared at each course by a 2 x 3 chi-square to determine whether the 3 groups differed during baseline, intervention, and post-intervention courses. Hypnotic susceptibility scores will be divided (high vs. low scores) and compared (2 x 2 chi-square) to change scores for nausea and vomiting. The significance of this investigation is its potential for improving the quality of life for children with cancer.

human therapy evaluation; meditation; ulcerative colitis; alternative medicine; clinical trial phase I; quality of life; clinical research; human subject;

[unreadable] DESCRIPTION (provided by applicant): Sex differences in adult laboratory (lab) and clinical pain prompted our original study of lab pain in 244 healthy children (8-17 years) to identify salient child factors underlying emerging sex differences found during adolescence in clinical pain patients. We examined puberty, sex, and psychological vulnerability and found some positive but inconsistent main effects and interactions in different pain response domains. Tolerance was greater for boys than girls in the pressure task and, controlling for age, cold pressor and pressure tolerance were greater for the late pubertal samples. Also, for cold and thermal tasks, boys increased their tolerance more than girls with increasing age, controlling for puberty. A derived variable, psychological vulnerability, was the strongest predictor of lab pain and was found to be a partial mediator between puberty and pain intensity. No highly salient sex or pubertal differences in children's pain, in or out of the lab, were found that could help explain sex differences seen in adult populations. Findings from our limited set of parent variables suggest that parent characteristics may be more potent than child factors in predicting children's pain. These key findings lead us, for this competing continuation study, to turn our attention to the inter-relationships between biopsychosocial maternal and paternal factors, child sex, pubertal status, and child chronic pain condition as predictors of children's lab and non-lab pain. We will study 240 children (8-17 yrs, 50 percent females, 50 percent late puberty, 50 percent with chronic headaches) and their mothers to assess non-lab pain history, pain-related disability, total bodily symptoms, negative affectivity, pain catastrophizing, gender-related expectations about pain, and parents' responses to children's pain. All mothers, children, and a subset of 50 fathers will individually undergo four lab pain tasks (cold, heat, pressure tolerance, and pressure pain sensitivity). Physiological, self-report, and behavioral lab pain responses will be assessed. All fathers will complete the questionnaires. The parent/child pain relationship offers a unique context within which to study critical components of the biopsychosocial pain model and the roles of sex and puberty. Our competing continuation study will advance our understanding of sex differences in pain, help identify children at risk by virtue of their pubertal status, sex, and parental influences, expand our knowledge of sex-related pain predictors, and provide pathways for intervention. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic, disabling disease that can compromise daily functioning, and health related quality of life (HRQOL), especially for young populations for whom long-term medication use can pose risks. This R21 project will compare a standardized group administered Iyengar Yoga program (IYP) for adolescents and young adults (AYA) with RA to a waitlist control condition comprised of standard care. IY is particularly suitable for clinical rehabilitation and research, as extensive and standardized teacher-training makes it replicable and safe. Our hypotheses are: 1) The IYP will be safe, acceptable and feasible for a young RA population, with <20% attrition;2) IYP participants will demonstrate significantly greater improvement on the primary outcomes of functioning and HRQOL relative to the control group following the 8 week IYP;treatment gains will be maintained at 2 months following completion of the IYP;3) IYP participants will also evidence significant improvement relative to controls on the secondary outcomes of pain, joint count, and mood. This project is built within a theoretical model purporting that Iyengar Yoga incorporates specific psychological and physical components that confer benefits on RA disability and HRQOL. Using a matched group design, 84 RA patients aged 16-21 years will receive an 8 week IYP (16 - 1.5 hour sessions twice weekly) or be assigned to the 8 week control condition, after which they will receive the 8 week IYP. Baseline, post-treatment, and two month follow-up assessments include standardized measures of general and arthritis-specific function, HRQOL, pain, mood, and inflamed joint count as well as qualitative interviews, and blood pressure/resting heart rate measurements. This study will be the first controlled evaluation of IYP for an AYA RA population and the study is grounded within a theoretical model that integrates the biopsychosocial model of rehabilitation. To maximize the knowledge gained from the study, we employ a quantitative/qualitative mixed methods approach to understanding treatment outcomes and predictors of treatment response. Ultimately our study will contribute to the development of a readily transportable IYP that may be used in multi-center trials and disseminated widely to other research and clinical settings, thus providing heuristic and practical value. Relevance: Conventional treatments for AYA with RA pose risks because of the need for long-term intervention. This study addresses the need for safe and effective rehabilitation approaches to RA by testing a standardized IY program within a rigorously conducted, theoretically-driven design to promote the science behind a treatment that could positively impact the lives of many young people with a disabling disease. PUBLIC HEALTH RELEVANCE: Conventional treatments for AYA with RA pose risks because of the need for long-term intervention. This project addresses the need for safe and effective rehabilitative approaches to RA by testing a standardized Iyengar Yoga program within a rigorously conducted, theoretically based study in order to provide the science behind a treatment that could positively impact the lives of many young people with disabling arthritis.

DESCRIPTION (provided by applicant): Chronic pain that persists or recurs for more than 3 months is now recognized as a significant problem that may affect 25-30 percent of children, with the prevalence increasing as children move into adolescence. Recurrent pain can severely limit a child's social, academic, and physical functioning, with long-term impact on his or her career path and quality of life. When pain persists and does not respond to standard treatment, adolescents over time will develop adaptive or maladaptive patterns of behavior that promote or inhibit continued functioning. Work within the cognitive-behavioral model has helped to show how maladaptive behaviors in response to pain may be reinforced and perpetuated by anxieties about the meaning of the pain, expectancies of harm and negative outcomes, and lack of self-efficacy to learn pain self-management skills. Cognitive-behavioral or coping skills therapies are often effective in teaching pain self- management skills to adults and adolescents, in helping to change maladaptive behaviors, and to improve functioning. But recent published models of pain management identify patient motivation as essential to a good outcome with these therapies. Patients who lack motivation to learn pain self-management, due to a low sense of self-efficacy or negative expectations of the value of learning these skills, may show little benefit. Even in an integrative pediatric pain clinic, where psychotherapy and many complementary and alternative therapies are offered, only adolescents with sufficient motivation will follow through on recommendations to participate in these therapies and learn pain self-management skills. Preliminary data from a recent multi-method study conducted by the investigators suggest that adolescent motivation to learn pain self- management may be reduced by lack of ongoing reinforcement after a clinic visit and/or by patients'perceptions of difference from peers and of isolation in an inexplicable illness. We propose to conduct a pilot study: an exploratory controlled trial of an innovative peer-mentorship intervention to model behavior and provide ongoing reinforcement to adolescents, relieve perceptions of difference, isolation and helplessness, and support and reinforce positive expectations and self-efficacy beliefs, using a structured protocol developed within a social learning model based on cognitive- behavioral theory. PUBLIC HEALTH RELEVANCE: Many American adolescents suffer from recurrent pain, which may impair their physical, social, and academic functioning. Although they may benefit from therapies that teach pain self-management skills, adolescents who feel isolated in their illness and have low expectations of benefiting from therapy may fail to participate or to persist in such therapies without sufficient reinforcement. This research will test a peer- mentorship intervention that may promote adherence and skills-building through modeling and reinforcement, with positive effects on physical, social and academic functioning.

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is characterized by painful vasoocclusive crises that occur on top of a chronic, progressive vascular disease. Advancement towards new treatment modalities for SCD has been significantly hampered by the lack of biomarkers that can effectively monitor the underlying pathophysiological processes. We have previously shown that SCD subjects have marked dysregulation of the autonomic nervous system (ANS), and that sigh and pain can cause vasoconstriction. We hypothesize that physiologically-based biomarkers reflecting regional perfusion and ANS balance report the collective effects of all molecular and cellular pathologies secondary to the gene defect in SCD. To study this hypothesis, we have assembled a group of skilled investigators from multiple disciplines (pain and behavioral research, biomedical engineering, cardiology, chemistry, hematology, physiology and biophysics, pulmonology, and radiology) to develop and calibrate biomarkers reflecting 1) cardiac ANS imbalance, peripheral and pain-triggered vasoconstriction; and 2) peripheral vascular function and regional cerebral flow and oxygenation. Another goal is to provide standardized measurement/processing tools for use by others. Our unique approach involves sampling multiple physiological variables simultaneously and using computational modeling to account for the complex interactions and isolate the biophysical biomarker of interest. Measurements will be made in human subjects with selected hematological disorders that differ in degree of anemia or blood rheology. We will also study SCD patients on chronic transfusion with varying percent hemoglobin S in order to separate the measurement components due to altered blood rheology and cardiac output from the components reflecting vascular status and the autonomic function of interest. The translation of these biomarkers and derived tools to the SCD research community will fulfill a need and be invaluable for stratifying risk, monitoring disease status, an measuring the effects of therapeutic interventions in patients with SCD. In the course of validating these biomarkers, we will improve our understanding of vascular disease in SCD and other hemoglobinopathies, as well as in normal subjects. (End of Abstract)

Sickle cell disease (SCD) is characterized by painful vasoocclusive crises that occur on top of a chronic, progressive vascular disease. Advancement towards new treatment modalities for SCD has been significantly hampered by the lack of biomarkers that can effectively monitor the underlying pathophysiological processes. We have previously shown that SCD subjects have marked dysregulation of the autonomic nervous system (ANS), and that sigh and pain can cause vasoconstriction. We hypothesize that physiologically-based biomarkers reflecting regional perfusion and ANS balance report the collective effects of all molecular and cellular pathologies secondary to the gene defect in SCD. To study this hypothesis, we have assembled a group of skilled investigators from multiple disciplines (pain and behavioral research, biomedical engineering, cardiology, chemistry, hematology, physiology and biophysics, pulmonology, and radiology) to develop and calibrate biomarkers reflecting 1) cardiac ANS imbalance, peripheral and pain-triggered vasoconstriction; and 2) peripheral vascular function and regional cerebral flow and oxygenation. Another goal is to provide standardized measurement/processing tools for use by others. Our unique approach involves sampling multiple physiological variables simultaneously and using computational modeling to account for the complex interactions and isolate the biophysical biomarker of interest. Measurements will be made in human subjects with selected hematological disorders that differ in degree of anemia or blood rheology. We will also study SCD patients on chronic transfusion with varying percent hemoglobin S in order to separate the measurement components due to altered blood rheology and cardiac output from the components reflecting vascular status and the autonomic function of interest. The translation of these biomarkers and derived tools to the SCD research community will fulfill a need and be invaluable for stratifying risk, monitoring disease status, and measuring the effects of therapeutic interventions in patients with SCD. In the course of validating these biomarkers, we will improve our understanding of vascular disease in SCD and other hemoglobinopathies, as well as in normal subjects. RELEVANCE (See instructions): Sickle cell disease, an inherited hemoglobin disorder, causes suffering and early death throughout the world. Progress for new therapy has been limited. We propose to develop/validate biomarkers of blood flow and autonomic nervous system dynamics that regulate vasoconstriction, and to translate these biomarkers into tools that other basic science or clinical investigators can use to provide objective assessments of therapies.